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  • 1.
    Aaltonen, Kristina E.
    et al.
    Lund University, Sweden.
    Rosendahl, Ann H.
    Lund University, Sweden; Skåne University Hospital, Sweden.
    Olsson, Hans
    Linköping University, Department of Clinical and Experimental Medicine, Division of Inflammation Medicine. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Center for Diagnostics, Department of Clinical Pathology and Clinical Genetics.
    Malmstrom, Per
    Lund University, Sweden; Skåne University Hospital, Sweden.
    Hartman, Linda
    Lund University, Sweden; Regional Cancer Centre South, Sweden.
    Ferno, Marten
    Lund University, Sweden.
    Association between insulin-like growth factor-1 receptor (IGF1R) negativity and poor prognosis in a cohort of women with primary breast cancer2014In: BMC Cancer, ISSN 1471-2407, E-ISSN 1471-2407, Vol. 14, no 794Article in journal (Refereed)
    Abstract [en]

    Background: Resistance towards endocrine therapy is a great concern in breast cancer treatment and may partly be explained by the activation of compensatory signaling pathways. The aim of the present study was to investigate if the insulin-like growth factor-1 receptor (IGF1R) signaling pathway was activated or deregulated in breast cancer patients and to explore if any of the markers were prognostic, with or without adjuvant tamoxifen. This signaling pathway has been suggested to cause estrogen independent cell growth and thus contribute to resistance to endocrine treatment in estrogen receptor (ER) positive breast cancer. Methods: The protein expression of IGF1R, phosphorylated Mammalian Target of Rapamycin (p-mTOR) and phosphorylated S6 ribosomal protein (p-S6rp) were investigated by immunohistochemistry using tissue microarrays in two patient cohorts. Cohort I (N = 264) consisted of mainly postmenopausal women with stage II breast cancer treated with tamoxifen for 2 years irrespective of ER status. Cohort II (N = 206) consisted of mainly medically untreated, premenopausal patients with node-negative breast cancer. Distant disease-free survival (DDFS) at 5 years was used as end-point for survival analyses. Results: We found that lower IGF1R expression was associated with worse prognosis for tamoxifen treated, postmenopausal women (HR = 0.70, 95% CI = 0.52 - 0.94, p = 0.016). The effect was seen mainly in ER-negative patients where the prognostic effect was retained after adjustment for other prognostic markers (adjusted HR = 0.49, 95% CI = 0.29 - 0.82, p = 0.007). Expression of IGF1R was associated with ER positivity (p less than 0.001) in the same patient cohort. Conclusions: Our results support previous studies indicating that IGF1R positivity reflects a well differentiated tumor with low metastatic capacity. An association between lack of IGF1R expression and worse prognosis was mainly seen in the ER-negative part of Cohort I. The lack of co-activation of downstream markers (p-mTOR and p-S6rp) in the IGF1R pathway suggested that the prognostic effect was not due to complete activation of this pathway. Thus, no evidence could be found for a compensatory function of IGF1R signaling in the investigated cohorts.

  • 2.
    Agholme, Lotta
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Health Sciences.
    Hallbeck, Martin
    Linköping University, Department of Clinical and Experimental Medicine, Division of Inflammation Medicine. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Center for Diagnostics, Department of Clinical Pathology and Clinical Genetics.
    Getting rid of intracellular Aβ- loss of cellular degradation leads to transfer between connected neurons2014In: Current pharmaceutical design, ISSN 1381-6128, E-ISSN 1873-4286, Vol. 20, no 15, p. 2458-2468Article in journal (Refereed)
    Abstract [en]

    The sporadic, late onset form of Alzheimers disease (AD) shares pathological hallmarks with the familial form; however, no clear reason for increased beta-amyloid (A beta) generation has been found in the former. It has long been speculated that the late onset form of AD is caused by reduced degradation and/or clearance of A beta. Indeed, both intracellular degradation systems, the proteasomal and lysosomal systems, have been shown to be defective in AD. Reduced proteasome activity increases levels of intracellular and secreted A beta. Furthermore, accumulation of improperly degraded A beta in the lysosomes causes lysosomal disruption and cell death. We recently showed that oligomeric A beta can be transmitted from one neuron to another, which causes neurotoxicity. In both the donating and receiving cells, A beta accumulates in the endo-lysosomal compartment. It is possible that ineffective degradation of A beta causes its transfer to neighboring neurons, thereby spreading AD pathology. This review summarizes the data underlying the idea of reduced A beta clearance and subsequent A beta spread in AD, and also suggests new therapeutic methods, which are aimed at targeting the degradation systems and synaptic transfer. By enhancing degradation of intracellular accumulated A beta, it can be possible to remove it and avoid A beta-induced neurodegeneration without disturbing the endogenously important pool of secreted A beta. Additionally, drugs targeted to inhibit the spread of intracellular toxic A beta aggregates may also be useful in stopping the progression of pathology, without affecting the level of A beta that normally occurs in the brain.

  • 3.
    Agholme, Lotta
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Geriatric. Linköping University, Faculty of Health Sciences.
    Hallbeck, Martin
    Linköping University, Department of Clinical and Experimental Medicine, Experimental Pathology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Diagnostics, Department of Clinical Pathology and Clinical Genetics.
    Benedikz, Eirikur
    Department of Neurobiology, Division of Neurodegeneration, Care Sciences and Society, Karolinska Institute, Stockholm, Sweden.
    Marcusson, Jan
    Linköping University, Department of Clinical and Experimental Medicine, Geriatric. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Local Health Care Services in Central Östergötland, Department of Geriatric Medicine.
    Kågedal, Katarina
    Linköping University, Department of Clinical and Experimental Medicine, Experimental Pathology. Linköping University, Faculty of Health Sciences.
    Amyloid-β Secretion, Generation, and Lysosomal Sequestration in Response to Proteasome Inhibition: Involvement of Autophagy2012In: Journal of Alzheimer's Disease, ISSN 1387-2877, E-ISSN 1875-8908, Vol. 31, no 2, p. 343-358Article in journal (Refereed)
    Abstract [en]

    The proteasome is important for degradation of worn out and misfolded proteins. Decreased proteasome activity has been implicated in Alzheimer's disease (AD). Proteasome inhibition induces autophagy, but it is still unknown whether autophagy is beneficial or deleterious to AD neurons, as the autophagosome has been suggested as a site of amyloid-β (Aβ) generation. In this study, we investigated the effect of proteasome inhibition on Aβ accumulation and secretion, as well as the processing of amyloid-β protein precursor (AβPP) in AβPPSwe transfected SH-SY5Y neuroblastoma cells. We show that proteasome inhibition resulted in autophagy-dependent accumulation of Aβ in lysosomes, and increased levels of intracellular and secreted Aβ. The enhanced levels of Aβ could not be explained by increased amounts of AβPP. Instead, reduced degradation of the C-terminal fragment of AβPP (C99) by the proteasome makes C99 available for γ-secretase cleavage, leading to Aβ generation. Inhibition of autophagy after proteasome inhibition led to reduced levels of intracellular, but not secreted Aβ, and tended to further increase the C99 to AβPP ratio, supporting involvement of the autophagosome in Aβ generation. Furthermore, proteasome inhibition caused a reduction in cellular viability, which was reverted by inhibition of autophagy. Dysfunction of the proteasome could cause lysosomal accumulation of Aβ, as well as increased generation and secretion of Aβ, which is partly facilitated by autophagy. As a decrease in cellular viability was also detected, it is possible that upregulation of autophagy is an unsuccessful rescue mechanism, which instead of being protective, contributes to AD pathogenesis.

  • 4.
    Agholme, Lotta
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuroscience. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Local Health Care Services in East Östergötland, Department of Geriatric Medicine in Norrköping.
    Nath, Sangeeta
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuroscience. Linköping University, Faculty of Health Sciences.
    Domert, Jakob
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuroscience. Linköping University, Faculty of Health Sciences.
    Marcusson, Jan
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuroscience. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Local Health Care Services in Central Östergötland, Department of Geriatric Medicine in Linköping.
    Kågedal, Katarina
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Health Sciences.
    Hallbeck, Martin
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuroscience. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Center for Diagnostics, Department of Clinical Pathology and Clinical Genetics.
    Proteasome Inhibition Induces Stress Kinase Dependent Transport Deficits – Implications for Alzheimer’s Disease2014In: Molecular and Cellular Neuroscience, ISSN 1044-7431, E-ISSN 1095-9327, Vol. 58, p. 29-39Article in journal (Refereed)
    Abstract [en]

    Alzheimer’s disease (AD) is characterized by accumulation of two misfolded and aggregated proteins, β-amyloid and hyperphosphorylated tau. Both cellular systems responsible for clearance of misfolded and aggregated proteins, the lysosomal and the proteasomal, have been shown to be malfunctioning in the aged brain and more so in AD patients. This malfunction could be the cause of β-amyloid and tau accumulation, eventually aggregating in plaques and tangles. We have investigated how decreased proteasome activity affects AD related pathophysiological changes of microtubule transport and stability, as well as tau phosphorylation. To do this, we used our recently developed neuronal model where human SH-SY5Y cells obtain neuronal morphology and function through differentiation. We found that exposure to low doses of the proteasome inhibitor MG-115 caused disturbed neuritic transport, together with microtubule destabilization and tau phosphorylation. Furthermore, reduced proteasome activity activated several kinases implicated in AD pathology, including JNK, c-Jun and ERK 1/2. Restoration of the microtubule transport was achieved by inhibiting ERK 1/2 activation, and simultaneous inhibition of both ERK 1/2 and c-Jun reversed the proteasome inhibition-induced tau phosphorylation. Taken together, this study suggests that a decrease in proteasome activity can, through activation of c-Jun and ERK 1/2, result in several events contributing to AD pathology. Restoring proteasome function or inhibiting ERK 1/2 and c-Jun could therefore be used as novel treatments against AD.

  • 5.
    Aneq Åström, Meriam
    et al.
    Linköping University, Department of Medical and Health Sciences, Clinical Physiology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart and Medicine Centre, Department of Clinical Physiology UHL.
    Fluur, Christina
    Östergötlands Läns Landsting, Heart and Medicine Centre, Department of Cardiology UHL.
    Rehnberg, Malin
    Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Health Sciences.
    Söderkvist, Peter
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Engvall, Jan
    Linköping University, Department of Medical and Health Sciences, Clinical Physiology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart and Medicine Centre, Department of Clinical Physiology UHL.
    Nylander, Eva
    Linköping University, Department of Medical and Health Sciences, Clinical Physiology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart and Medicine Centre, Department of Clinical Physiology UHL.
    Gunnarsson, Cecilia
    Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Diagnostics, Department of Clinical Pathology and Clinical Genetics.
    Novel plakophilin2 mutation. Three generation family with arrhythmogenic right ventricular cardiomyopathy2012In: Scandinavian Cardiovascular Journal, ISSN 1401-7431, E-ISSN 1651-2006, Vol. 46, no 2, p. 72-75Article in journal (Refereed)
    Abstract [en]

    Objectives: The autosomal dominant form of arrhythmogenic right ventricular cardiomyopathy (ARVC)has been linked to mutations in desmosomal proteins. Different studies have shown that amutation in plakophilin-2 (PKP 2) is a frequent genetic cause for ARVC. We describe a newmutation in the PKP2 gene, the genotype-phenotype variation in this mutation and its clinicalconsequences.

    Design: Individuals in a three generation family were investigated after the sudden cardiac death of a young male. Clinical evaluation, electrocardiography, echocardiography, magnetic resonance imaging, endomyocardial biopsy and genetic testing were performed.

    Results: A novel heterozygote mutation, a c.368G>A transition, located in exon 3 of the PKP2 gene was found (p.Trp123X). The phenotype was characterized by arrhythmia at an early age in some individuals, with mild abnormalities on imaging. However a relative carrying this mutation, with positive findings on endomyocardial biopsy had an otherwise normal phenotype, for 16 years, whereas a relative fulfilling the modified Task Force Criteria for ARVC turned out to be a non-carrier.

    Conclusions: This shows the variable penetrance and phenotypic expression in ARVC and highlights the need of genetic testing as well as a thorough phenotype examination as a part of the investigations in ARVC pedigrees.

  • 6.
    Antoniou, Antonis C.
    et al.
    Center for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, United Kingdom.
    Beesley, Jonathan
    Queensland Institute of Medical Research, Brisbane, Australia.
    McGuffog, Lesley
    University Cambridge, Centre Canc Genet Epidemiol, Department Publ Hlth and Primary Care, Cambridge, England.
    M. Sinilnikova, Olga
    Unité Mixte de Génétique Constitutionnelle des Cancers Fréquents, Centre Hospitalier Universitaire de Lyon/Centre Léon Bérard, Lyon, France.
    Healey, Sue
    Queensland Institute Med Research, Brisbane, Qld, Australia.
    L. Neuhausen, Susan
    Beckman Research Institute City Hope, Department Populat Science, Duarte, CA USA.
    Chun Ding, Yuan
    Beckman Research Institute City Hope, Department Populat Science, Duarte, CA USA.
    R. Rebbeck, Timothy
    University Penn, Sch Med, Abramson Canc Centre, Philadelphia, PA 19104 USA.
    N. Weitzel, Jeffrey
    City Hope Natl Med Centre, Duarte, CA 91010 USA.
    T. Lynch, Henry
    Creighton University, Omaha, NE 68178 USA.
    Isaacs, Claudine
    A. Ganz, Patricia
    University Calif Los Angeles, Jonsson Comprehens Canc Centre, Los Angeles, CA 90024 USA.
    Tomlinson, Gail
    University Texas Hlth Science Centre San Antonio, San Antonio, TX 78229 USA.
    I. Olopade, Olufunmilayo
    University Chicago, Med Centre, Chicago, IL 60637 USA.
    J. Couch, Fergus
    Mayo Clin, Department Lab Med and Pathol, Rochester, MN USA.
    Wang, Xianshu
    Mayo Clin, Department Lab Med and Pathol, Rochester, MN USA.
    M. Lindor, Noralane
    Mayo Clin, Department Med Genet, Rochester, MN USA.
    S. Pankratz, Vernon
    Mayo Clin, Department Hlth Science Research, Rochester, MN USA.
    Radice, Paolo
    Fdn IRCCS Ist Nazl Tumori INT, Unit Genet Susceptibil Canc, Department Expt Oncol and Mol Med, Milan, Italy.
    Manoukian, Siranoush
    Fdn IRCCS Ist Nazl Tumori INT, Unit Med Genet, Department Prevent and Predict Med, Milan, Italy.
    Peissel, Bernard
    Fdn IRCCS Ist Nazl Tumori INT, Unit Med Genet, Department Prevent and Predict Med, Milan, Italy.
    Zaffaroni, Daniela
    Fdn IRCCS Ist Nazl Tumori INT, Unit Med Genet, Department Prevent and Predict Med, Milan, Italy.
    Barile, Monica
    IEO, Div Canc Prevent and Genet, Milan, Italy.
    Viel, Alessandra
    IRCCS, CRO, Div Expt Oncol 1, Aviano, PN, Italy.
    Allavena, Anna
    University Turin, Department Genet Biol and Biochem, Turin, Italy.
    DallOlio, Valentina
    Cogentech, Consortium Genom Technology, Milan, Italy.
    Peterlongo, Paolo
    Fdn IRCCS Ist Nazl Tumori INT, Unit Genet Susceptibil Canc, Department Expt Oncol and Mol Med, Milan, Italy.
    I. Szabo, Csilla
    Mayo Clin, Coll Med, Department Lab Med and Pathol, Rochester, MN USA.
    Zikan, Michal
    Charles University Prague, Fac Med 1, Department Biochem and Expt Oncol, Prague, Czech Republic.
    Claes, Kathleen
    Ghent University Hospital, Centre Med Genet, B-9000 Ghent, Belgium.
    Poppe, Bruce
    Ghent University Hospital, Centre Med Genet, B-9000 Ghent, Belgium.
    Foretova, Lenka
    Masaryk Mem Canc Institute, Department Canc Epidemiol and Genet, Brno, Czech Republic.
    L. Mai, Phuong
    US Natl Canc Institute, Clin Genet Branch, Rockville, MD USA.
    H. Greene, Mark
    US Natl Canc Institute, Clin Genet Branch, Rockville, MD USA.
    Rennert, Gad
    Technion Israel Institute Technology, Carmel Med Centre, Haifa, Israel.
    Lejbkowicz, Flavio
    Technion Israel Institute Technology, Carmel Med Centre, Haifa, Israel.
    Glendon, Gord
    OCGN, Toronto, ON, Canada.
    Ozcelik, Hilmi
    Mt Sinai Hospital, Fred A Litwin Centre Canc Genet, Samuel Lunenfeld Research Institute, New York, NY 10029 USA.
    L. Andrulis, Irene
    OCGN, Toronto, ON, Canada.
    Thomassen, Mads
    Odense University Hospital, Department Clin Genet, DK-5000 Odense, Denmark.
    Gerdes, Anne-Marie
    Rigshosp, Department Clin Genet, Odense, Denmark.
    Sunde, Lone
    Aalborg Hospital, Department Clin Genet, Aalborg, Denmark.
    Cruger, Dorthe
    Vejle Hospital, Department Clin Genet, Velje, Denmark.
    Birk Jensen, Uffe
    Aarhus University Hospital, Department Clin Genet, DK-8000 Aarhus, Denmark.
    Caligo, Maria
    University Pisa, Div Surg Mol and Ultrastruct Pathol, Department Oncol, Pisa, Italy.
    Friedman, Eitan
    Sheba Med Centre, Susanne Levy Gertner Oncogenet Unit, Tel Hashomer, Israel.
    Kaufman, Bella
    Sheba Med Centre, Institute Oncol, Tel Hashomer, Israel.
    Laitman, Yael
    Sheba Med Centre, Susanne Levy Gertner Oncogenet Unit, Tel Hashomer, Israel.
    Milgrom, Roni
    Sheba Med Centre, Susanne Levy Gertner Oncogenet Unit, Tel Hashomer, Israel.
    Dubrovsky, Maya
    Sheba Med Centre, Susanne Levy Gertner Oncogenet Unit, Tel Hashomer, Israel.
    Cohen, Shimrit
    Sheba Med Centre, Susanne Levy Gertner Oncogenet Unit, Tel Hashomer, Israel.
    Borg, Ake
    Lund University, Department Oncol, Lund, Sweden.
    Jernstroem, Helena
    Lund University, Department Oncol, Lund, Sweden.
    Lindblom, Annika
    Karolinska Institute, Department Mol Med and Surg, Stockholm, Sweden.
    Rantala, Johanna
    Karolinska Institute, Department Mol Med and Surg, Stockholm, Sweden.
    Stenmark Askmalm, Marie
    Linköping University, Department of Clinical and Experimental Medicine, Oncology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Diagnostics, Department of Clinical Pathology and Clinical Genetics.
    Melin, Beatrice
    Umea University, Department Radiat Science, Umea, Sweden.
    Nathanson, Kate
    University Penn, Philadelphia, PA 19104 USA.
    Domchek, Susan
    University Penn, Philadelphia, PA 19104 USA.
    Jakubowska, Ania
    Pomeranian Med University, Int Hereditary Canc Centre, Department Genet and Pathol, Szczecin, Poland.
    Lubinski, Jan
    Pomeranian Med University, Int Hereditary Canc Centre, Department Genet and Pathol, Szczecin, Poland.
    Huzarski, Tomasz
    Pomeranian Med University, Int Hereditary Canc Centre, Department Genet and Pathol, Szczecin, Poland.
    Osorio, Ana
    Spanish Natl Canc Research Centre, Human Genet Grp, Human Canc Genet Programme, Madrid, Spain.
    Lasa, Adriana
    Hospital Santa Creu and Sant Pau, Genet Serv, Barcelona, Spain.
    Duran, Mercedes
    University Valladolid, Institute Biol and Mol Genet, IBGM UVA, Valladolid, Spain.
    Tejada, Maria-Isabel
    Cruces Hospital Barakaldo, Mol Genet Lab, Department Biochem, Bizkaia, Spain.
    Godino, Javier
    University Lozano Blesa, Hospital Clin, Oncol Serv, Zaragoza, Spain.
    Benitez, Javier
    Spanish Natl Canc Research Centre, Human Canc Genet Programme, Genotyping Unit, Madrid, Spain.
    Hamann, Ute
    Deutsch Krebsforschungszentrum, Mol Genet Breast Canc, D-6900 Heidelberg, Germany.
    Kriege, Mieke
    Daniel Denhoed Canc Centre, Erasmus MC, Department Med Oncol, Family Canc Clin, Rotterdam, Netherlands.
    Hoogerbrugge, Nicoline
    Radboud University Nijmegen, Nijmegen Med Centre, Hereditary Canc Clin, NL-6525 ED Nijmegen, Netherlands.
    B. van der Luijt, Rob
    University Med Centre Utrecht, Department Med Genet, Utrecht, Netherlands.
    J. van Asperen, Christi
    Leiden University, Med Centre, Department Clin Genet, Leiden, Netherlands.
    Devilee, Peter
    Leiden University, Department Human Genet, Med Centre, Department Pathol, NL-2300 RA Leiden, Netherlands.
    J. Meijers-Heijboer, E.
    Vrije University Amsterdam Med Centre, Department Clin Genet, Amsterdam, Netherlands.
    J. Blok, Marinus
    University Med Centre, Department Genet and Cell Biol, Maastricht, Netherlands.
    M. Aalfs, Cora
    University Amsterdam, Acad Med Centre, Department Clin Genet, NL-1105 AZ Amsterdam, Netherlands.
    Hogervorst, Frans
    Netherlands Canc Institute, Family Canc Clin, Amsterdam, Netherlands.
    Rookus, Matti
    Netherlands Canc Institute, Department Epidemiol, Amsterdam, Netherlands.
    Cook, Margaret
    University Cambridge, Centre Canc Genet Epidemiol, Department Publ Hlth and Primary Care, Cambridge, England.
    Oliver, Clare
    University Cambridge, Centre Canc Genet Epidemiol, Department Publ Hlth and Primary Care, Cambridge, England.
    Frost, Debra
    University Cambridge, Centre Canc Genet Epidemiol, Department Publ Hlth and Primary Care, Cambridge, England.
    Conroy, Don
    University Cambridge, Department Oncol, Cambridge, England.
    Gareth Evans, D.
    Cent Manchester University Hospital NHS Fdn Trust, Manchester Acad Hlth Science Centre, Manchester, Lancs, England.
    Lalloo, Fiona
    Cent Manchester University Hospital NHS Fdn Trust, Manchester Acad Hlth Science Centre, Manchester, Lancs, England.
    Pichert, Gabriella
    Guys and St Thomas NHS Fdn Trust, London, England.
    Davidson, Rosemarie
    Ferguson Smith Centre Clin Genet, Glasgow, Lanark, Scotland.
    Cole, Trevor
    Birmingham Womens Hospital Healthcare NHS Trust, W Midlands Reg Genet Serv, Birmingham, W Midlands, England.
    Cook, Jackie
    Sheffield Childrens Hospital, Sheffield Clin Genet Serv, Sheffield, S Yorkshire, England.
    Paterson, Joan
    Addenbrookes Hospital, Department Clin Genet, E Anglian Reg Genet Serv, Cambridge, England.
    Hodgson, Shirley
    University London, Department Clin Genet, St Georges Hospital, London, England.
    J. Morrison, Patrick
    Belfast City Hospital, Northern Ireland Reg Genet Centre, Belfast BT9 7AD, Antrim, North Ireland.
    E. Porteous, Mary
    Western Gen Hospital, SE Scotland Reg Genet Serv, Edinburgh EH4 2XU, Midlothian, Scotland.
    Walker, Lisa
    Churchill Hospital, Oxford Reg Genet Serv, Oxford OX3 7LJ, England.
    John Kennedy, M.
    St James Hospital, Canc Genet Program, Hope Directorate, Dublin, Ireland.
    Dorkins, Huw
    Kennedy Galton Centre, NW Thames Reg Genet Serv, Harrow, Middx, England.
    Peock, Susan
    University Cambridge, Centre Canc Genet Epidemiol, Department Publ Hlth and Primary Care, Cambridge, England.
    K. Godwin, Andrew
    Fox Chase Canc Centre, Department Med Oncol, Womens Canc Program, Philadelphia, PA 19111 USA.
    Stoppa-Lyonnet, Dominique
    University Paris 05, INSERM, U509, Serv Genet Oncol,Institute Curie, Paris, France.
    de Pauw, Antoine
    University Paris 05, INSERM, U509, Serv Genet Oncol,Institute Curie, Paris, France.
    Mazoyer, Sylvie
    University Lyon 1, CNRS, Centre Leon Berard, Equipe Labellisee LIGUE 2008,UMR5201, F-69365 Lyon, France.
    Bonadona, Valerie
    University Lyon 1, CNRS, UMR5558, F-69365 Lyon, France.
    Lasset, Christine
    University Lyon 1, CNRS, UMR5558, F-69365 Lyon, France.
    Dreyfus, Helene
    CHU Grenoble, Department Genet, F-38043 Grenoble, France.
    Leroux, Dominique
    CHU Grenoble, Department Genet, F-38043 Grenoble, France.
    Hardouin, Agnes
    Centre Francois Baclesse, F-14021 Caen, France.
    Berthet, Pascaline
    Centre Francois Baclesse, F-14021 Caen, France.
    Faivre, Laurence
    Centre Hospital University Dijon, Centre Genet, Dijon, France.
    Loustalot, Catherine
    Centre Lutte Canc Georges Francois Leclerc, Dijon, France.
    Noguchi, Tetsuro
    INSERM, Institute Paoli Calmettes, UMR599, Department Oncol Genet, F-13258 Marseille, France.
    Sobol, Hagay
    INSERM, Institute Paoli Calmettes, UMR599, Department Oncol Genet, F-13258 Marseille, France.
    Rouleau, Etienne
    Centre Rene Huguenin, INSERM, U735, St Cloud, France.
    Nogues, Catherine
    Frenay, Marc
    Centre Antoine Lacassagne, F-06054 Nice, France.
    Venat-Bouvet, Laurence
    Centre Hospital University Limoges, Department Oncol, Limoges, France.
    L. Hopper, John
    University Melbourne, Melbourne, Vic, Australia.
    B. Daly, Mary
    Fox Chase Canc Centre, Department Med Oncol, Womens Canc Program, Philadelphia, PA 19111 USA.
    B. Terry, Mary
    Columbia University, New York, NY USA.
    M. John, Esther
    Canc Prevent Institute Calif, Fremont, CA USA.
    S. Buys, Saundra
    University Utah, Hlth Science Centre, Huntsman Canc Institute, Salt Lake City, UT USA.
    Yassin, Yosuf
    Dana Farber Canc Institute, Boston, MA 02115 USA.
    Miron, Alexander
    Dana Farber Canc Institute, Boston, MA 02115 USA.
    Goldgar, David
    University Utah, Department Dermatol, Salt Lake City, UT USA.
    F. Singer, Christian
    Med University Vienna, Department Obstet and Gynecol, Vienna, Austria.
    Catharina Dressler, Anne
    Med University Vienna, Department Obstet and Gynecol, Vienna, Austria.
    Gschwantler-Kaulich, Daphne
    Med University Vienna, Department Obstet and Gynecol, Vienna, Austria.
    Pfeiler, Georg
    Med University Vienna, Department Obstet and Gynecol, Vienna, Austria.
    V. O. Hansen, Thomas
    University Copenhagen, Rigshosp, Department Clin Biochem, DK-2100 Copenhagen, Denmark.
    Jnson, Lars
    University Copenhagen, Rigshosp, Department Clin Biochem, DK-2100 Copenhagen, Denmark.
    A. Agnarsson, Bjarni
    University Hospital, Department Pathol, Reykjavik, Iceland.
    Kirchhoff, Tomas
    Mem Sloan Kettering Canc Centre, Department Med, Clin Genet Serv, New York, NY 10021 USA.
    Offit, Kenneth
    Mem Sloan Kettering Canc Centre, Department Med, Clin Genet Serv, New York, NY 10021 USA.
    Devlin, Vincent
    Mem Sloan Kettering Canc Centre, Department Med, Clin Genet Serv, New York, NY 10021 USA.
    Dutra-Clarke, Ana
    Mem Sloan Kettering Canc Centre, Department Med, Clin Genet Serv, New York, NY 10021 USA.
    Piedmonte, Marion
    Roswell Pk Canc Institute, GOG Stat and Data Centre, Buffalo, NY 14263 USA.
    C. Rodriguez, Gustavo
    NorthShore University Hlth Syst, Evanston NW Healthcare, Evanston, IL USA.
    Wakeley, Katie
    Tufts University, New England Med Centre, Boston, MA 02111 USA.
    F. Boggess, John
    University N Carolina, Chapel Hill, NC USA.
    Basil, Jack
    St Elizabeth Hospital, Edgewood, KY USA.
    E. Schwartz, Peter
    Yale University, Sch Med, New Haven, CT USA.
    V. Blank, Stephanie
    NYU, Sch Med, New York, NY USA.
    Ewart Toland, Amanda
    Ohio State University, Centre Comprehens Canc, Department Internal Med and Mol Virol, Div Human Canc Genet, Columbus, OH 43210 USA.
    Montagna, Marco
    IRCCS, Ist Oncol Veneto, Immunol and Mol Oncol Unit, Padua, Italy.
    Casella, Cinzia
    IRCCS, Ist Oncol Veneto, Immunol and Mol Oncol Unit, Padua, Italy.
    Imyanitov, Evgeny
    NN Petrov Institute Oncol, St Petersburg, Russia.
    Tihomirova, Laima
    Latvian Biomed Research and Study Centre, Riga, Latvia.
    Blanco, Ignacio
    Catalan Institute Oncol IDIBELL, Hereditary Canc Program, Barcelona, Spain.
    Lazaro, Conxi
    Catalan Institute Oncol IDIBELL, Hereditary Canc Program, Barcelona, Spain.
    J. Ramus, Susan
    University London Imperial Coll Science Technology and Med, Gynaecol Oncol Unit, UCL EGA Institute Womens Hlth, London, England.
    Sucheston, Lara
    Roswell Pk Canc Institute, Department Canc Prevent and Control, Buffalo, NY 14263 USA.
    Y. Karlan, Beth
    Cedars Sinai Med Centre, Womens Canc Research Institute, Samuel Oschin Comprehens Canc Institute, Los Angeles, CA 90048 USA.
    Gross, Jenny
    Cedars Sinai Med Centre, Womens Canc Research Institute, Samuel Oschin Comprehens Canc Institute, Los Angeles, CA 90048 USA.
    Schmutzler, Rita
    University Cologne, Centre Familial Breast and Ovarian Canc, Department Obstet and Gynaecol, Cologne, Germany.
    Wappenschmidt, Barbara
    University Cologne, Centre Familial Breast and Ovarian Canc, Department Obstet and Gynaecol, Cologne, Germany.
    Engel, Christoph
    University Leipzig, Institute Med Informat Stat and Epidemiol, Leipzig, Germany.
    Meindl, Alfons
    Tech University Munich, Klinikum Rechts Isar, Department Obstet and Gynaecol, Div Tumor Genet, D-8000 Munich, Germany.
    Lochmann, Magdalena
    Tech University Munich, Klinikum Rechts Isar, Department Obstet and Gynaecol, Div Tumor Genet, D-8000 Munich, Germany.
    Arnold, Norbert
    University Kiel, Department Obstet and Gynaecol, University Hospital Schleswig Holstein, Kiel, Germany.
    Heidemann, Simone
    University Kiel, Institute Human Genet, University Hospital Schleswig Holstein, Kiel, Germany.
    Varon-Mateeva, Raymonda
    Campus Virchow Klinikum, Charite Berlin, Institute Human Genet, Berlin, Germany.
    Niederacher, Dieter
    University Dusseldorf, Department Obstet and Gynaecol, Div Mol Genet, University Hospital Dusseldorf, Dusseldorf, Germany.
    Sutter, Christian
    University Heidelberg, Institute Human Genet, Div Mol Diagnost, Heidelberg, Germany.
    Deissler, Helmut
    University Hospital Ulm, Department Obstet and Gynaecol, Ulm, Germany.
    Gadzicki, Dorothea
    Hannover Med Sch, Institute Cell and Mol Pathol, D-3000 Hannover, Germany.
    Preisler-Adams, Sabine
    University Hospital Muenster, Institute Human Genet, Munster, Germany.
    Kast, Karin
    Tech University Dresden, Department Obstet and Gynaecol, University Hospital Carl Gustav Carus, Dresden, Germany.
    Schoenbuchner, Ines
    University Wurzburg, Institute Human Genet, Div Med Genet, Wurzburg, Germany.
    Caldes, Trinidad
    Hospital Clin San Carlos, Mol Oncol Lab, Madrid, Spain.
    de la Hoya, Miguel
    Hospital Clin San Carlos, Mol Oncol Lab, Madrid, Spain.
    Aittomaeki, Kristiina
    University Helsinki, Cent Hospital, Department Clin Genet, Helsinki, Finland.
    Nevanlinna, Heli
    University Helsinki, Cent Hospital, Department Obstet and Gynecol, FIN-00290 Helsinki, Finland.
    Simard, Jacques
    Centre Hospital University Quebec, Canada Research Chair Oncogenet, Canc Genom Lab, Quebec City, PQ, Canada.
    B. Spurdle, Amanda
    Queensland Institute Med Research, Brisbane, Qld, Australia.
    Holland, Helene
    Queensland Institute Med Research, Brisbane, Qld, Australia.
    Chen, Xiaoqing
    Queensland Institute Med Research, Brisbane, Qld, Australia.
    Platte, Radka
    Center for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, United Kingdom.
    Chenevix-Trench, Georgia
    Queensland Institute of Medical Research, Brisbane, Australia.
    F. Easton, Douglas
    University Chicago, Med Centre, Chicago, IL 60637 USA.
    Common Breast Cancer Susceptibility Alleles and the Risk of Breast Cancer for BRCA1 and BRCA2 Mutation Carriers: Implications for Risk Prediction2010In: Cancer Research, ISSN 0008-5472, E-ISSN 1538-7445, Vol. 70, no 23, p. 9742-9754Article in journal (Refereed)
    Abstract [en]

    The known breast cancer susceptibility polymorphisms in FGFR2, TNRC9/TOX3, MAP3K1, LSP1, and 2q35 confer increased risks of breast cancer for BRCA1 or BRCA2 mutation carriers. We evaluated the associations of 3 additional single nucleotide polymorphisms (SNPs), rs4973768 in SLC4A7/NEK10, rs6504950 in STXBP4/COX11, and rs10941679 at 5p12, and reanalyzed the previous associations using additional carriers in a sample of 12,525 BRCA1 and 7,409 BRCA2 carriers. Additionally, we investigated potential interactions between SNPs and assessed the implications for risk prediction. The minor alleles of rs4973768 and rs10941679 were associated with increased breast cancer risk for BRCA2 carriers (per-allele HR = 1.10, 95% CI: 1.03–1.18, P = 0.006 and HR = 1.09, 95% CI: 1.01–1.19, P = 0.03, respectively). Neither SNP was associated with breast cancer risk for BRCA1 carriers, and rs6504950 was not associated with breast cancer for either BRCA1 or BRCA2 carriers. Of the 9 polymorphisms investigated, 7 were associated with breast cancer for BRCA2 carriers (FGFR2, TOX3, MAP3K1, LSP1, 2q35, SLC4A7, 5p12, P = 7 × 10−11 − 0.03), but only TOX3 and 2q35 were associated with the risk for BRCA1 carriers (P = 0.0049, 0.03, respectively). All risk-associated polymorphisms appear to interact multiplicatively on breast cancer risk for mutation carriers. Based on the joint genotype distribution of the 7 risk-associated SNPs in BRCA2 mutation carriers, the 5% of BRCA2 carriers at highest risk (i.e., between 95th and 100th percentiles) were predicted to have a probability between 80% and 96% of developing breast cancer by age 80, compared with 42% to 50% for the 5% of carriers at lowest risk. Our findings indicated that these risk differences might be sufficient to influence the clinical management of mutation carriers. Cancer Res; 70(23); 9742–54. ©2010 AACR.

  • 7.
    Appelqvist, Hanna
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Experimental Pathology. Linköping University, Faculty of Health Sciences.
    Johansson, Ann-Charlotte
    Linköping University, Department of Clinical and Experimental Medicine, Experimental Pathology. Linköping University, Faculty of Health Sciences.
    Linderoth, Emma
    Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Health Sciences.
    Johansson, Uno
    Linköping University, Department of Clinical and Experimental Medicine, Experimental Pathology. Linköping University, Faculty of Health Sciences.
    Antonsson, Bruno
    Geneva Research Centre, Switzerland .
    Steinfeld, Robert
    University of Medical Centre Gottingen, Germany .
    Kågedal, Katarina
    Linköping University, Department of Clinical and Experimental Medicine, Experimental Pathology. Linköping University, Faculty of Health Sciences.
    Öllinger, Karin
    Linköping University, Department of Clinical and Experimental Medicine, Experimental Pathology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Diagnostics, Department of Clinical Pathology and Clinical Genetics.
    Lysosome-Mediated Apoptosis is Associated with Cathepsin D-Specific Processing of Bid at Phe24,Trp48, and Phe1832012In: Annals of Clinical and Laboratory Science, ISSN 0091-7370, E-ISSN 1550-8080, Vol. 42, no 3, p. 231-242Article in journal (Refereed)
    Abstract [en]

    Bax-mediated permeabilization of the outer mitochondrial membrane and release of apoptogenic factors into the cytosol are key events that occur during apoptosis. Likewise, apoptosis is associated with permeabilization of the lysosomal membrane and release of lysosomal cathepsins into the cytosol. This report identifies proteolytically active cathepsin D as an important component of apoptotic signaling following lysosomal membrane permeabilization in fibroblasts. Lysosome-mediated cell death is associated with degradation of Bax sequestering 14-3-3 proteins, cleavage of the Box activator Bid, and translocation of Box to mitochondria, all of which were cathepsin D-dependent. Processing of Bid could be reproduced by enforced lysosomal membrane permeabilization, using the lysosomotropic detergent O-methyl-serine dodecylamine hydrochloride (MSDH). We identified three cathepsin D-specific cleavage sites in Bid, Phe24, Trp48, and Phe183. Cathepsin D-cleaved Bid induced Bax-mediated release of cytochrome c from purified mitochondria, indicating that the fragments generated are functionally active. Moreover, apoptosis was associated with cytosolic acidification, thereby providing a more favorable environment for the cathepsin D-mediated cleavage of Bid. Our study suggests that cytosolic cathepsin D triggers Bax-mediated cytochrome c release by proteolytic activation of Bid.

  • 8.
    Appelqvist, Hanna
    et al.
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, The Institute of Technology.
    Wäster, Petra
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Health Sciences.
    Eriksson, Ida
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Health Sciences.
    Rosdahl, Inger
    Linköping University, Department of Clinical and Experimental Medicine, Division of Inflammation Medicine. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart and Medicine Center, Department of Dermatology and Venerology.
    Öllinger, Karin
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Center for Diagnostics, Department of Clinical Pathology and Clinical Genetics.
    Lysosomal exocytosis and caspase-8-mediated apoptosis in UVA-irradiated keratinocytes2013In: Journal of Cell Science, ISSN 0021-9533, E-ISSN 1477-9137, Vol. 126, no 24, p. 5578-5584Article in journal (Refereed)
    Abstract [en]

    Ultraviolet (UV) irradiation is a major environmental carcinogen involved in the development of skin cancer. To elucidate the initial signaling during UV-induced damage in human keratinocytes, we investigated lysosomal exocytosis and apoptosis induction. UVA, but not UVB, induced plasma membrane damage, which was repaired by Ca2+-dependent lysosomal exocytosis. The lysosomal exocytosis resulted in extracellular release of cathepsin D and acid sphingomyelinase (aSMase). Two hours after UVA irradiation, we detected activation of caspase-8, which was reduced by addition of anti-aSMAse. Furthermore, caspase-8 activation and apoptosis was reduced by prevention of endocytosis and by the use of cathepsin inhibitors. We conclude that lysosomal exocytosis is part of the keratinocyte response to UVA and is followed by cathepsin-dependent activation of caspase-8. The findings have implications for the understanding of UV-induced skin damage and emphasize that UVA and UVB initiate apoptosis through different signaling pathways in keratinocytes.

  • 9.
    Appelqvist, Hanna
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Health Sciences.
    Wäster, Petra
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Health Sciences.
    Kågedal, Katarina
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Health Sciences.
    Öllinger, Karin
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Center for Diagnostics, Department of Clinical Pathology and Clinical Genetics.
    The lysosome: from waste bag to potential therapeutic target2013In: Journal of Molecular Cell Biology, ISSN 1674-2788, E-ISSN 1759-4685, Vol. 5, no 4, p. 214-226Article, review/survey (Refereed)
    Abstract [en]

    Lysosomes are ubiquitous membrane-bound intracellular organelles with an acidic interior. They are central for degradation and recycling of macromolecules delivered by endocytosis, phagocytosis, and autophagy. In contrast to the rather simplified view of lysosomes as waste bags, nowadays lysosomes are recognized as advanced organelles involved in many cellular processes and are considered crucial regulators of cell homeostasis. The function of lysosomes is critically dependent on soluble lysosomal hydrolases (e.g. cathepsins) as well as lysosomal membrane proteins (e.g. lysosome-associated membrane proteins). This review focuses on lysosomal involvement in digestion of intra- and extracellular material, plasma membrane repair, cholesterol homeostasis, and cell death. Regulation of lysosomal biogenesis and function via the transcription factor EB (TFEB) will also be discussed. In addition, lysosomal contribution to diseases, including lysosomal storage disorders, neurodegenerative disorders, cancer, and cardiovascular diseases, is presented.

  • 10.
    Benner, Axel
    et al.
    German Cancer Research Centre, Germany.
    Mansouri, Larry
    Uppsala University, Sweden.
    Rossi, Davide
    Amedeo Avogadro University of Eastern Piedmont, Italy.
    Majid, Aneela
    University of Leicester, England.
    Willander, Kerstin
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Haematology.
    Parker, Anton
    Royal Bournemouth Hospital, England.
    Bond, Gareth
    University of Oxford, England.
    Pavlova, Sarka
    Masaryk University, Czech Republic; Masaryk University, Czech Republic.
    Nueckel, Holger
    University of Duisburg Essen, Germany.
    Merkel, Olaf
    Paracelus Medical University, Austria.
    Ghia, Paolo
    University of Bita Salute San Raffaele, Italy.
    Montserrat, Emili
    University of Barcelona, Spain.
    Arifin Kaderi, Mohd
    Uppsala University, Sweden; Int Islamic University of Malaysia, Malaysia.
    Rosenquist, Richard
    Uppsala University, Sweden.
    Gaidano, Gianluca
    Amedeo Avogadro University of Eastern Piedmont, Italy.
    Dyer, Martin J. S.
    University of Leicester, England.
    Söderkvist, Peter
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Center for Diagnostics, Department of Clinical Pathology and Clinical Genetics.
    Linderholm, Mats
    Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Health Sciences.
    Oscier, David
    Royal Bournemouth Hospital, England.
    Tvaruzkova, Zuzana
    Masaryk University, Czech Republic; Masaryk University, Czech Republic.
    Pospisilova, Sarka
    Masaryk University, Czech Republic; Masaryk University, Czech Republic.
    Duehrsen, Ulrich
    University of Duisburg Essen, Germany.
    Greil, Richard
    Paracelus Medical University, Austria.
    Doehner, Hartmut
    University of Ulm, Germany.
    Stilgenbauer, Stephan
    University of Ulm, Germany.
    Zenz, Thorsten
    German Cancer Research Centre, Germany; University of Heidelberg Hospital, Germany.
    MDM2 promotor polymorphism and disease characteristics in chronic lymphocytic leukemia: results of an individual patient data-based meta-analysis2014In: Haematologica (online), ISSN 0390-6078, E-ISSN 1592-8721, Vol. 99, no 8, p. 1285-1291Article in journal (Refereed)
    Abstract [en]

    A number of single nucleotide polymorphisms have been associated with disease predisposition in chronic lymphocytic leukemia. A single nucleotide polymorphism in the MDM2 promotor region, MDM2SNP309, was shown to soothe the p53 pathway. In the current study, we aimed to clarify the effect of the MDM2SNP309 on chronic lymphocytic leukemia characteristics and outcome. We performed a meta-analysis of data from 2598 individual patients from 10 different cohorts. Patients data and genetic analysis for MDM2SNP309 genotype, immunoglobulin heavy chain variable region mutation status and fluorescence in situ hybridization results were collected. There were no differences in overall survival based on the polymorphism (log rank test, stratified by study cohort; P=0.76; GG genotype: cohort-adjusted median overall survival of 151 months; TG: 153 months; TT: 149 months). In a multivariable Cox proportional hazards regression analysis, advanced age, male sex and unmutated immunoglobulin heavy chain variable region genes were associated with inferior survival, but not the MDM2 genotype. The MDM2SNP309 is unlikely to influence disease characteristics and prognosis in chronic lymphocytic leukemia. Studies investigating the impact of individual single nucleotide polymorphisms on prognosis are often controversial. This may be due to selection bias and small sample size. A meta-analysis based on individual patient data provides a reasonable strategy for prognostic factor analyses in the case of small individual studies. Individual patient data-based meta-analysis can, therefore, be a powerful tool to assess genetic risk factors in the absence of large studies.

  • 11.
    Bergfors, Elisabet
    et al.
    Linköping University, Department of Medical and Health Sciences. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Local Health Care Services in West Östergötland, Research & Development Unit in Local Health Care.
    Lundmark, Katarzyna
    Linköping University, Department of Clinical and Experimental Medicine, Division of Inflammation Medicine. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Center for Diagnostics, Department of Clinical Pathology and Clinical Genetics.
    Nyström Kronander, Ulla
    Linköping University, Department of Clinical and Experimental Medicine, Allergy Centre. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart and Medicine Center, Allergy Center.
    A child with a long-standing, intensely itching subcutaneous nodule on a thigh: an uncommon (?) reaction to commonly used vaccines2013In: BMJ Case Reports, ISSN 1757-790XArticle in journal (Refereed)
    Abstract [en]

    A 2-year-old girl presented with an intensely itching subcutaneous nodule on the front of a thigh. The nodule persisted for 10 months until it was excised. Subsequent investigation for malignancy and systemic disease showed no pathological findings. The diagnosis, persistent itching vaccination granuloma, was revealed by hazard almost 2 years after the onset of symptoms. Persistent itching subcutaneous nodules at the injection site for aluminium containing vaccines (mostly diphtheria-tetanus-pertussis combination vaccines for primary immunisation of infants) may appear with a long delay after the vaccination (months), cause prolonged itching (years) and are often associated with contact allergy to aluminium. The condition is poorly recognised in Health Care which may lead to prolonged symptoms and unnecessary investigations.

  • 12.
    Björnsson, Bergthor
    et al.
    Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Health Sciences.
    Winbladh, Anders
    Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Health Sciences.
    Bojmar, Linda
    Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Health Sciences.
    Trulsson, Lena
    Linköping University, Department of Clinical and Experimental Medicine, Surgery. Linköping University, Faculty of Health Sciences.
    Olsson, Hans
    Linköping University, Department of Clinical and Experimental Medicine, Molecular and Immunological Pathology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Diagnostics, Department of Clinical Pathology and Clinical Genetics.
    Sundqvist, Tommy
    Linköping University, Department of Clinical and Experimental Medicine, Medical Microbiology. Linköping University, Faculty of Health Sciences.
    Gullstrand, Per
    Östergötlands Läns Landsting, Centre for Surgery, Orthopaedics and Cancer Treatment, Department of Surgery UHL.
    Sandström, Per
    Linköping University, Department of Clinical and Experimental Medicine, Surgery. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Surgery, Orthopaedics and Cancer Treatment, Department of Surgery in Östergötland.
    Remote or Conventional Ischemic Preconditioning -Local Liver Metabolism in Rats Studied with Microdialysis2012In: Journal of Surgical Research, ISSN 0022-4804, E-ISSN 1095-8673, Vol. 176, no 1, p. 55-62Article in journal (Refereed)
    Abstract [en]

    Background. Ischemic preconditioning (IPC) of the liver decreases liver injury secondary to ischemia and reperfusion. An attractive alternative to IPC is remote ischemic preconditioning (R-IPC), but these two methods have not previously been compared. Material and Methods. Eighty-seven rats were randomized into four groups: sham operated (n = 15), 1 h segmental ischemia (IRI, n = 24), preceeded by IPC (n = 24), or R-IPC (n = 24) (to the left hindleg). IPC and R-IPC were performed with 10 min ischemia and 10 min of reperfusion. Analyses of liver microdialysate (MD), serum transaminase levels, and liver histology were made. Results. Rats treated with IPC and R-IPC had significantly lower AST, 71.5 (19.6) IU/L respective 96.6 (12.4) at 4 h reperfusion than those subjected to IRI alone, 155 (20.9), P = 0.0004 and P = 0.04 respectively. IPC also had lower ALT levels, 41.6 (11.3) IU/L than had IRI 107.4 (15.5), P = 0.003. The MD glycerol was significantly higher during ischemia in the R-IPC = 759 (84) mu M] and the IRI = 732 (67)] groups than in the IPC 514 (70) group, P = 0.022 and P = 0.046 respectively. The MD glucose after ischemia was lower in the IPC group 7.1 (1.2) than in the IRI group 12.7 (1.6), P = 0.005. Preconditioning to the liver caused an direct increase in lactate, glucose and glycerol in the ischemic segment compared with the control segment an effect not seen in the R-IPC and IRI groups. Conclusions. IPC affects glucose metabolism in the rat liver, observed with MD. IPC reduces liver cell injury during ischemic and reperfusion in rats. R-IPC performed over the same length of time as IPC does not have the same effect as the latter on ALT levels and MD glycerol; this may suggest that R-IPC does not offer the same protection as IPC in this setting of rat liver IRI.

  • 13.
    Bojmar, Linda
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Health Sciences.
    Karlsson, Elin
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Health Sciences.
    Ellegård, Sander
    Linköping University, Department of Clinical and Experimental Medicine, Oncology. Linköping University, Faculty of Health Sciences.
    Olsson, Hans
    Linköping University, Department of Clinical and Experimental Medicine, Molecular and Immunological Pathology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Center for Diagnostics, Department of Clinical Pathology and Clinical Genetics.
    Björnsson, Bergthor
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Surgery in Linköping.
    Hallböök, Olof
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Surgery in Linköping.
    Larsson, Marie
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Health Sciences.
    Stål, Olle
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Oncology.
    Sandström, Per
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Surgery in Linköping.
    The Role of MicroRNA-200 in Progression of Human Colorectal and Breast Cancer2013In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 8, no 12, p. 84815-Article in journal (Refereed)
    Abstract [en]

    The role of the epithelial-mesenchymal transition (EMT) in cancer has been studied extensively in vitro, but involvement of the EMT in tumorigenesis in vivo is largely unknown. We investigated the potential of microRNAs as clinical markers and analyzed participation of the EMT-associated microRNA-200 ZEB E-cadherin pathway in cancer progression. Expression of the microRNA-200 family was quantified by real-time RT-PCR analysis of fresh-frozen and microdissected formalin-fixed paraffin-embedded primary colorectal tumors, normal colon mucosa, and matched liver metastases. MicroRNA expression was validated by in situ hybridization and after in vitro culture of the malignant cells. To assess EMT as a predictive marker, factors considered relevant in colorectal cancer were investigated in 98 primary breast tumors from a treatment-randomized study. Associations between the studied EMTmarkers were found in primary breast tumors and in colorectal liver metastases. MicroRNA-200 expression in epithelial cells was lower in malignant mucosa than in normal mucosa, and was also decreased in metastatic compared to non-metastatic colorectal cancer. Low microRNA-200 expression in colorectal liver metastases was associated with bad prognosis. In breast cancer, low levels of microRNA-200 were related to reduced survival and high expression of microRNA-200 was predictive of benefit from radiotheraphy. MicroRNA-200 was associated with ER positive status, and inversely correlated to HER2 and overactivation of the PI3K/AKT pathway, that was associated with high ZEB1 mRNA expression. Our findings suggest that the stability of microRNAs makes them suitable as clinical markers and that the EMT-related microRNA-200 - ZEB - E-cadherin signaling pathway is connected to established clinical characteristics and can give useful prognostic and treatment-predictive information in progressive breast and colorectal cancers.

  • 14.
    Bourghardt Peebo, Beatrice
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Ophthalmology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Sinnescentrum, Department of Ophthalmology UHL/MH.
    Fagerholm, Per
    Linköping University, Department of Clinical and Experimental Medicine, Ophthalmology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Sinnescentrum, Department of Ophthalmology UHL/MH.
    Traneus-Rockert, Catharina
    Östergötlands Läns Landsting, Centre for Diagnostics, Department of Clinical Pathology and Clinical Genetics.
    Lagali, Neil
    Linköping University, Department of Clinical and Experimental Medicine, Ophthalmology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Sinnescentrum, Department of Ophthalmology UHL/MH.
    Cellular level characterization of capillary regression in inflammatory angiogenesis using an in vivo corneal model2011In: Angiogenesis, ISSN 0969-6970, E-ISSN 1573-7209, Vol. 14, no 3, p. 393-405Article in journal (Refereed)
    Abstract [en]

    In this study, we introduce a technique for repeated, microscopic observation of single regressing capillaries in vivo in inflamed murine corneas. Natural capillary regression was initiated by removal of inflammatory stimulus during an active pro-angiogenic phase, while the additional impact of anti-angiogenic treatment with triamcinolone or bevazicumab was investigated. Capillaries regressed naturally within 1 week and treatments did not further enhance the natural regression. Morphologically, early-phase regression was characterized by significant lumen narrowing and a significant reduction in CD11b+ myeloid cell infiltration of the extracellular matrix. By 1 week, vascular remodeling occurred concomitant with CD11b+CD68+KiM2R+ mature macrophage localization on capillary walls. Empty conduits without blood flow, positive for collagen IV and devoid of vascular endothelium and pericytes, were apparent in vivo and by 3 weeks were more numerous than perfused capillaries. By 3 weeks, macrophages aggregated around remaining perfused capillaries and were observed in apposition with degrading capillary segments. Abrupt termination of capillary sprouting in our regression model further revealed vascular endothelial abandonment of sprout tips and perfused capillary loop formation within a single angiogenic sprout, possibly as an intussusceptive response to cessation of the stimulus. Finally, we observed lumen constriction and macrophage localization on capillary walls in vivo in a clinical case of corneal capillary regression that paralleled findings in our murine model.

  • 15.
    Bourghardt Peebo, Beatrice
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Ophthalmology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Sinnescentrum, Department of Ophthalmology UHL/MH.
    Fagerholm, Per
    Linköping University, Department of Clinical and Experimental Medicine, Ophthalmology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Sinnescentrum, Department of Ophthalmology UHL/MH.
    Traneus-Rockert, Catharina
    Östergötlands Läns Landsting, Centre for Diagnostics, Department of Clinical Pathology and Clinical Genetics.
    Lagali, Neil
    Linköping University, Department of Clinical and Experimental Medicine, Ophthalmology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Sinnescentrum, Department of Ophthalmology UHL/MH.
    Time-Lapse In Vivo Imaging of Corneal Angiogenesis: The Role of Inflammatory Cells in Capillary Sprouting2011In: Investigative Ophthalmology and Visual Science, ISSN 0146-0404, E-ISSN 1552-5783, Vol. 52, no 6, p. 3060-3068Article in journal (Refereed)
    Abstract [en]

    PURPOSE. To elucidate the temporal sequence of events leading to new capillary sprouting in inflammatory corneal angiogenesis.

    METHODS. Angiogenesis was induced by corneal suture placement in Wistar rats. The inflamed region was examined by time-lapse in vivo confocal microscopy for up to 7 days. At 6 and 12 hours and 1, 2, 4, and 7 days, corneas were excised for flat mount immunofluorescence with primary antibodies for CD31, CD34, CD45, CD11b, CD11c, Ki-M2R, NG2, and alpha-SMA. From days 0 to 4, the in vivo extravasation and expansion characteristics of single limbal vessels were quantified.

    RESULTS. Starting hours after induction and peaking at day 1, CD45(+)CD11b(+) myeloid cells extravasated from limbal vessels and formed endothelium-free tunnels within the stroma en route to the inflammatory stimulus. Limbal vessel diameter tripled on days 2 to 3 as vascular buds emerged and transformed into perfused capillary sprouts less than 1 day later. A subset of spindle-shaped CD11b(+) myeloid-lineage cells, but not dendritic cells or mature macrophages, appeared to directly facilitate further capillary sprout growth. These cells incorporated into vascular endothelium near the sprout tip, co-expressing endothelial marker CD31. Sprouts had perfusion characteristics distinct from feeder vessels and many sprout tips were open-ended.

    CONCLUSIONS. Time-lapse in vivo corneal confocal microscopy can be used to track a temporal sequence of events in corneal angiogenesis. The technique has revealed potential roles for myeloid cells in promoting vessel sprouting in an inflammatory corneal setting.

  • 16.
    Cauvi, David M
    et al.
    Department of Surgery, University of California, San Diego, 9500 Gilman Drive, No. 0739, La Jolla, CA 92093-0739, USA.
    Gabriel, Rodney
    Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, CA 92037, USA.
    Kono, Dwight H
    Department of Immunology and Microbial Science, The Scripps Research Institute, La Jolla, CA 92037, USA.
    Hultman, Per
    Linköping University, Department of Clinical and Experimental Medicine, Division of Inflammation Medicine. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Center for Diagnostics, Department of Clinical Pathology and Clinical Genetics.
    Pollard, K Michael
    Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, CA 92037, USA.
    A tandem repeat in decay accelerating factor 1 is associated with severity of murine mercury-induced autoimmunity2014In: Autoimmune Diseases, ISSN 2090-0422, E-ISSN 2090-0430, Vol. 2014, no 260613Article in journal (Refereed)
    Abstract [en]

    Decay accelerating factor (DAF), a complement-regulatory protein, protects cells from bystander complement-mediated lysis and negatively regulates T cells. Reduced expression of DAF occurs in several systemic autoimmune diseases including systemic lupus erythematosus, and DAF deficiency exacerbates disease in several autoimmune models, including murine mercury-induced autoimmunity (mHgIA). Daf1, located within Hmr1, a chromosome 1 locus associated in DBA/2 mice with resistance to mHgIA, could be a candidate. Here we show that reduced Daf1 transcription in lupus-prone mice was not associated with a reduction in the Daf1 transcription factor SP1. Studies of NZB mice congenic for the mHgIA-resistant DBA/2 Hmr1 locus suggested that Daf1 expression was controlled by the host genome and not the Hmr1 locus. A unique pentanucleotide repeat variant in the second intron of Daf1 in DBA/2 mice was identified and shown in F2 intercrosses to be associated with less severe disease; however, analysis of Hmr1 congenics indicated that this most likely reflected the presence of autoimmunity-predisposing genetic variants within the Hmr1 locus or that Daf1 expression is mediated by the tandem repeat in epistasis with other genetic variants present in autoimmune-prone mice. These studies argue that the effect of DAF on autoimmunity is complex and may require multiple genetic elements.

  • 17.
    Cauvi, DM
    et al.
    The Scripps Institute, La Jolla, CA, USA.
    Pollard, KM
    The Scripps Institute, La Jolla, CA, USA.
    Hultman, Per
    Linköping University, Department of Clinical and Experimental Medicine, Molecular and Immunological Pathology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Diagnostics, Department of Clinical Pathology and Clinical Genetics.
    Autoimmune models2010In: Comprehensive Toxicology / [ed] Charlene A. McQueen, Oxford: Academic Press , 2010, 2, p. 413-438Chapter in book (Other academic)
    Abstract [en]

    Toxicology is the study of the nature and actions of chemicals on biological systems. In more primitive times, it really was the study of poisons. However, in the early 1500s, it was apparent to Paracelsus that "the dose differentiates a poison and a remedy". Clearly, the two most important tenets of toxicology were established during that time. The level of exposure (dose) and the duration of exposure (time) will determine the degree and nature of a toxicological response.

  • 18.
    Dahle, Charlotte
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Clinical Immunology. Linköping University, Faculty of Health Sciences.
    Hagman, A.
    Östergötlands Läns Landsting, Centre for Diagnostics, Department of Clinical Immunology and Transfusion Medicine.
    Ignatova, Simone
    Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Diagnostics, Department of Clinical Pathology and Clinical Genetics.
    Ström, Magnus
    Linköping University, Department of Clinical and Experimental Medicine, Gastroenterology and Hepatology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart and Medicine Centre, Department of Endocrinology and Gastroenterology UHL.
    Antibodies against deamidated gliadin peptides identify adult coeliac disease patients negative for antibodies against endomysium and tissue transglutaminase2010In: Alimentary Pharmacology and Therapeutics, ISSN 0269-2813, E-ISSN 1365-2036, Vol. 32, no 2, p. 254-260Article in journal (Refereed)
    Abstract [en]

    Background This study was done to evaluate the diagnostic utility of antibodies against deamidated gliadin peptides compared to traditional markers for coeliac disease. Aim To evaluate diagnostic utility of antibodies against deamidated gliadin peptide (DGP). Methods Sera from 176 adults, referred for endoscopy without previous analysis of antibodies against tissue transglutaminase (tTG) or endomysium (EmA), were retrospectively analysed by ELISAs detecting IgA/IgG antibodies against DGP or a mixture of DGP and tTG, and compared with IgA-tTG and EmA. Seventy-nine individuals were diagnosed with coeliac disease. Results Receiver operating characteristic analyses verified the manufacturers cut-off limits except for IgA/IgG-DGP/ tTG. In sera without IgA deficiency, the sensitivity was higher for IgA/IgG-DGP (0.85-0.87) compared with IgA-tTg (0.76) and EmA (0.61). All tests showed high specificity (0.95-1.00). Eighteen coeliac disease-sera were negative regarding IgA-tTG, nine of which were positive for IgA/IgG-DGP. Sera from coeliac disease-patients greater than70 years were more often negative for IgA-tTG (50%) and IgA/IgG-DGP (36%) than younger patients (15% and 8% respectively) (P less than 0.01). Three of the four IgA-deficient patients were positive in the IgA/IgG-DGP assay. Conclusions In this study of patients unselected regarding IgA-tTg/EmA, thus unbiased in this respect, IgA/IgG-DGP identified adult coeliac disease patients negative for antibodies against endomysium and tissue transglutaminase. Serology is often negative in elderly patients with coeliac disease; a small bowel biopsy should therefore be performed generously before coeliac disease is excluded.

  • 19.
    Danbolt, Christina
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuroscience. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Center for Diagnostics, Department of Clinical Pathology and Clinical Genetics.
    Hult, Peter
    Linköping University, Department of Biomedical Engineering, Physiological Measurements. Linköping University, Faculty of Arts and Sciences.
    Grahn, Lita Tibbling
    Ask, Per
    Linköping University, Department of Biomedical Engineering, Physiological Measurements. Linköping University, The Institute of Technology.
    Validation and characterization of the computerized laryngeal analyzer (CLA) technique.1999In: Dysphagia (New York. Print), ISSN 0179-051X, E-ISSN 1432-0460, Vol. 14, no 4, p. 191-195Article in journal (Refereed)
    Abstract [en]

    The aim of this study was to investigate the response characteristics of the Computerized Laryngeal Analyzer (CLA) and the validity of the noninvasive CLA method to detect swallowing-induced laryngeal elevation correctly. Two healthy adults and two experimental models were used in the study. The CLA technique identified all swallowing events but was unable to discriminate between swallowing and other movements of the tongue or the neck. The computer program produced a derivated response to a square wave signal. Stepwise bending increments of the sensor displayed a linear amplitude response. The degree of laryngeal elevation could not be estimated with the CLA technique, and it was not possible to draw any reliable conclusions from the recordings as to whether the larynx was moving upward or downward.

  • 20.
    Ding, Yuan C
    et al.
    City Hope National Medical Centre, CA, USA .
    McGuffog, Lesley
    University of Cambridge Worts Causeway, England .
    Healey, Sue
    Royal Brisbane Hospital, Australia .
    Friedman, Eitan
    Chaim Sheba Medical Centre, Israel Chaim Sheba Medical Centre, Israel Tel Aviv University, Israel .
    Laitman, Yael
    Chaim Sheba Medical Centre, Israel Chaim Sheba Medical Centre, Israel Tel Aviv University, Israel .
    Paluch-Shimon, Shani
    Chaim Sheba Medical Centre, Israel Chaim Sheba Medical Centre, Israel Tel Aviv University, Israel .
    Kaufman, Bella
    Chaim Sheba Medical Centre, Israel Chaim Sheba Medical Centre, Israel Tel Aviv University, Israel .
    Liljegren, Annelie
    Karolinska University Hospital, Sweden .
    Lindblom, Annika
    Karolinska University Hospital, Sweden .
    Olsson, Hakan
    University of Lund Hospital, Sweden .
    Kristoffersson, Ulf
    University of Lund Hospital, Sweden .
    Stenmark Askmalm, Marie
    Linköping University, Department of Clinical and Experimental Medicine, Oncology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Diagnostics, Department of Clinical Pathology and Clinical Genetics.
    Melin, Beatrice
    Umeå University, Sweden .
    Domchek, Susan M
    University of Penn, PA, USA .
    Nathanson, Katherine L
    University of Penn, PA, USA .
    Rebbeck, Timothy R
    University of Penn, PA, USA .
    Jakubowska, Anna
    Pomeranian Medical University, Poland .
    Lubinski, Jan
    Pomeranian Medical University, Poland .
    Jaworska, Katarzyna
    Pomeranian Medical University, Poland .
    Durda, Katarzyna
    Pomeranian Medical University, Poland .
    Gronwald, Jacek
    Pomeranian Medical University, Poland .
    Huzarski, Tomasz
    Pomeranian Medical University, Poland .
    Cybulski, Cezary
    Pomeranian Medical University, Poland .
    Byrski, Tomasz
    Pomeranian Medical University, Poland .
    Osorio, Ana
    Spanish National Cancer Research Centre, Spain Spanish National Cancer Research Centre, Spain Spanish Network Rare Disease CIBERER, Spain .
    Ramony Cajal, Teresa
    Hospital Santa Creu and Sant Pau, Spain .
    Stavropoulou, Alexandra V
    National Centre Science Research Demokritos, Greece .
    Benitez, Javier
    Spanish National Cancer Research Centre, Spain Spanish National Cancer Research Centre, Spain Spanish Network Rare Disease CIBERER, Spain .
    Hamann, Ute
    Deutsch Krebsforschungszentrum DKFZ, Germany .
    Rookus, Matti
    Netherlands Cancer Institute, Netherlands .
    Aalfs, Cora M
    University of Amsterdam, Netherlands .
    de Lange, Judith L
    Netherlands Cancer Institute, Netherlands .
    Meijers-Heijboer, Hanne E J
    Vrije University of Amsterdam Medical Centre, Netherlands .
    Oosterwijk, Jan C
    University of Groningen, Netherlands .
    van Asperen, Christi J
    Leiden University, Netherlands .
    Gomez Garcia, Encarna B
    MUMC, Netherlands .
    Hoogerbrugge, Nicoline
    Radboud University of Nijmegen, Netherlands .
    Jager, Agnes
    Erasmus University, Netherlands .
    van der Luijt, Rob B
    University of Medical Centre Utrecht, Netherlands .
    Easton, Douglas F
    University of Cambridge, England .
    Peock, Susan
    University of Cambridge, England .
    Frost, Debra
    University of Cambridge, England .
    Ellis, Steve D
    University of Cambridge, England .
    Platte, Radka
    University of Cambridge, England .
    Fineberg, Elena
    University of Cambridge, England .
    Evans, D Gareth
    Central Manchester University Hospital NHS Fdn Trust, England .
    Lalloo, Fiona
    Central Manchester University Hospital NHS Fdn Trust, England .
    Izatt, Louise
    Guys and St Thomas NHS Fdn Trust, England .
    Eeles, Ros
    Institute Cancer Research, England Royal Marsden NHS Fdn Trust, England .
    Adlard, Julian
    Yorkshire Regional Genet Serv, England .
    Davidson, Rosemarie
    Yorkhill Hospital, Scotland .
    Eccles, Diana
    University Hospital Southampton NHS Fdn Trust, England .
    Cole, Trevor
    Birmingham Womens Hospital Healthcare NHS Trust, England .
    Cook, Jackie
    Sheffield Childrens Hospital, England .
    Brewer, Carole
    Royal Devon and Exeter Hospital, England .
    Tischkowitz, Marc
    University of Cambridge, England .
    Godwin, Andrew K
    University of Kansas, KS, USA .
    Pathak, Harsh
    University of Kansas, KS, USA .
    Stoppa-Lyonnet, Dominique
    Institute Curie, France Institute Curie, France University of Paris 05, France .
    Sinilnikova, Olga M
    University of Lyon 1, France Centre Hospital University of Lyon, France .
    Mazoyer, Sylvie
    University of Lyon 1, France .
    Barjhoux, Laure
    University of Lyon 1, France .
    Leone, Melanie
    Centre Hospital University of Lyon, France .
    Gauthier-Villars, Marion
    Institute Curie, France .
    Caux-Moncoutier, Virginie
    Institute Curie, France .
    de Pauw, Antoine
    Institute Curie, France .
    Hardouin, Agnes
    Centre Francois Baclesse, France .
    Berthet, Pascaline
    Centre Francois Baclesse, France .
    Dreyfus, Helene
    CHU Grenoble, France University of Grenoble, France .
    Fert Ferrer, Sandra
    Hotel Dieu Centre Hospital, France .
    Collonge-Rame, Marie-Agnes
    CHU Besancon, France .
    Sokolowska, Johanna
    Nancy University, France .
    Buys, Saundra
    University of Utah, UT, USA .
    Daly, Mary
    Fox Chase Cancer Centre, PA, USA .
    Miron, Alex
    Dana Farber Cancer Institute, MA, USA .
    Terry, Mary Beth
    Columbia University, NY, USA .
    Chung, Wendy
    Columbia University, NY, USA .
    John, Esther M
    Cancer Prevent Institute Calif, CA, USA Stanford University, CA, USA Stanford Cancer Institute, CA, USA .
    Southey, Melissa
    University of Melbourne, Australia .
    Goldgar, David
    University of Utah, UT, USA .
    Singer, Christian F
    Medical University of Vienna, Austria .
    Tea, Muy-Kheng Maria
    Medical University of Vienna, Austria .
    Gschwantler-Kaulich, Daphne
    Medical University of Vienna, Austria .
    Fink-Retter, Anneliese
    Medical University of Vienna, Austria .
    Hansen, Thomas V O
    Copenhagen University Hospital, Denmark .
    Ejlertsen, Bent
    Copenhagen University Hospital, Denmark .
    Johannsson, Oskar T
    Landspitali University Hospital, Iceland University of Iceland, Iceland .
    Offit, Kenneth
    Clin Cancer Genet Lab, NY, USA .
    Sarrel, Kara
    Clin Cancer Genet Lab, NY, USA .
    Gaudet, Mia M
    Amer Cancer Soc, GA, USA .
    Vijai, Joseph
    Clin Cancer Genet Lab, NY, USA .
    Robson, Mark
    Mem Sloan Kettering Cancer Centre, NY, USA .
    Piedmonte, Marion R
    Roswell Pk Cancer Institute, NY, USA .
    Andrews, Lesley
    Australia New Zealand Gynaecol Oncology Grp, Australia .
    Cohn, David
    Ohio State University, OH, USA .
    DeMars, Leslie R
    Dartmouth Hitchcock Medical Centre, NH, USA .
    DiSilvestro, Paul
    Brown University, RI, USA .
    Rodriguez, Gustavo
    NorthShore University of Health Syst, IL, USA .
    Ewart Toland, Amanda
    Ohio State University, OH, USA Ohio State University, OH, USA .
    Montagna, Marco
    Ist Oncology Veneto IOV IRCCS, Italy .
    Agata, Simona
    Ist Oncology Veneto IOV IRCCS, Italy .
    Imyanitov, Evgeny
    NN Petrov Oncology Research Institute, Russia .
    Isaacs, Claudine
    Georgetown University, DC, USA .
    Janavicius, Ramunas
    Vilnius University Hospital, Lithuania .
    Lazaro, Conxi
    Institute Catala Oncol, Spain .
    Blanco, Ignacio
    IDIBELL Catalan Institute Oncol, Spain .
    Ramus, Susan J
    University of So Calif, CA, USA .
    Sucheston, Lara
    Roswell Pk Cancer Institute, NY, USA .
    Karlan, Beth Y
    Cedars Sinai Medical Centre, CA, USA .
    Gross, Jenny
    Cedars Sinai Medical Centre, CA, USA .
    Ganz, Patricia A
    University of Calif Los Angeles, CA, USA .
    Beattie, Mary S
    University of Calif San Francisco, CA, USA .
    Schmutzler, Rita K
    University Hospital Cologne, Germany .
    Wappenschmidt, Barbara
    University Hospital Cologne, Germany .
    Meindl, Alfons
    Technical University of Munich, Germany .
    Arnold, Norbert
    University of Kiel, Germany .
    Niederacher, Dieter
    University of Dusseldorf, Germany .
    Preisler-Adams, Sabine
    University of Munster, Germany .
    Gadzicki, Dorotehea
    Hannover Medical Sch, Germany .
    Varon-Mateeva, Raymonda
    Charite, Germany .
    Deissler, Helmut
    University Hospital Ulm, Germany .
    Gehrig, Andrea
    University of Wurzburg, Germany .
    Sutter, Christian
    University of Heidelberg Hospital, Germany .
    Kast, Karin
    Technical University of Dresden, Germany .
    Nevanlinna, Heli
    University of Helsinki, Finland .
    Aittomaki, Kristiina
    Centre Hospital University of Quebec, Canada University of Laval, Canada .
    Spurdle, Amanda B
    Royal Brisbane Hospital, Australia .
    Beesley, Jonathan
    Royal Brisbane Hospital, Australia .
    Chen, Xiaoqing
    Royal Brisbane Hospital, Australia .
    Tomlinson, Gail E
    University of Texas Health Science Centre San Antonio, TX, USA.
    Weitzel, Jeffrey
    City Hope National Medical Centre, CA, USA .
    Garber, Judy E
    Harvard University, MA, USA .
    Olopade, Olufunmilayo I
    University of Chicago, IL, USA .
    Rubinstein, Wendy S
    NorthShore University of HealthSyst, IL, USA .
    Tung, Nadine
    Beth Israel Deaconess Medical Centre, MA, USA .
    Blum, Joanne L
    Baylor Charles A Sammons Cancer Centre, TX, USA .
    Narod, Steven A
    Womens Coll Hospital, Canada .
    Brummel, Sean
    Harvard University, MA, USA .
    Gillen, Daniel L
    University of Calif Irvine, CA USA .
    Lindor, Noralane
    Mayo Clin, MN, USA .
    Fredericksen, Zachary
    Mayo Clin, MN, USA .
    Pankratz, Vernon S
    Mayo Clin, MN, USA .
    Couch, Fergus J
    Mayo Clin, MN, USA .
    Radice, Paolo
    Fdn IRCCS Ist Nazl Tumori INT, Italy Fdn Ist FIRC Oncology Mol, Italy .
    Peterlongo, Paolo
    Fdn IRCCS Ist Nazl Tumori INT, Italy Fdn Ist FIRC Oncology Mol, Italy .
    Greene, Mark H
    NCI, MD, USA .
    Loud, Jennifer T
    NCI, MD, USA .
    Mai, Phuong L
    NCI, MD, USA .
    Andrulis, Irene L
    University of Toronto, Canada .
    Glendon, Gord
    University of Toronto, Canada .
    Gerdes, Anne-Marie
    Odense University Hospital, Denmark .
    Birk Jensen, Uffe
    Skejby Hospital, Denmark .
    Skytte, Anne-Bine
    Vejle Hospital, Denmark .
    Caligo, Maria A
    University of Pisa, Italy University Hospital Pisa, Italy .
    Lee, Andrew
    University of Cambridge Worts Causeway, England .
    Chenevix-Trench, Georgia
    Royal Brisbane Hospital, Australia .
    Antoniou, Antonis C
    University of Cambridge Worts Causeway, England .
    Neuhausen, Susan L
    City Hope National Medical Centre, CA, USA .
    A Nonsynonymous Polymorphism in IRS1 Modifies Risk of Developing Breast and Ovarian Cancers in BRCA1 and Ovarian Cancer in BRCA2 Mutation Carriers2012In: Cancer Epidemiology, Biomarkers and Prevention, ISSN 1055-9965, E-ISSN 1538-7755, Vol. 21, no 8, p. 1362-1370Article in journal (Refereed)
    Abstract [en]

    Background: We previously reported significant associations between genetic variants in insulin receptor substrate 1 (IRS1) and breast cancer risk in women carrying BRCA1 mutations. The objectives of this study were to investigate whether the IRS1 variants modified ovarian cancer risk and were associated with breast cancer risk in a larger cohort of BRCA1 and BRCA2 mutation carriers. less thanbrgreater than less thanbrgreater thanMethods: IRS1 rs1801123, rs1330645, and rs1801278 were genotyped in samples from 36 centers in the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA). Data were analyzed by a retrospective cohort approach modeling the associations with breast and ovarian cancer risks simultaneously. Analyses were stratified by BRCA1 and BRCA2 status and mutation class in BRCA1 carriers. less thanbrgreater than less thanbrgreater thanResults: Rs1801278 (Gly972Arg) was associated with ovarian cancer risk for both BRCA1 (HR, 1.43; 95% confidence interval (CI), 1.06-1.92; P = 0.019) and BRCA2 mutation carriers (HR, 2.21; 95% CI, 1.39-3.52, P = 0.0008). For BRCA1 mutation carriers, the breast cancer risk was higher in carriers with class II mutations than class I mutations (class II HR, 1.86; 95% CI, 1.28-2.70; class I HR, 0.86; 95%CI, 0.69-1.09; P-difference, 0.0006). Rs13306465 was associated with ovarian cancer risk in BRCA1 class II mutation carriers (HR, 2.42; P = 0.03). less thanbrgreater than less thanbrgreater thanConclusion: The IRS1 Gly972Arg single-nucleotide polymorphism, which affects insulin-like growth factor and insulin signaling, modifies ovarian cancer risk in BRCA1 and BRCA2 mutation carriers and breast cancer risk in BRCA1 class II mutation carriers. less thanbrgreater than less thanbrgreater thanImpact: These findings may prove useful for risk prediction for breast and ovarian cancers in BRCA1 and BRCA2 mutation carriers.

  • 21.
    Domert, Jakob
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Health Sciences.
    Rao, Sahana Bhima
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Health Sciences.
    Agholme, Lotta
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Health Sciences.
    Brorsson, Ann-Christin
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, The Institute of Technology.
    Marcusson, Jan
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuroscience. Linköping University, Faculty of Health Sciences.
    Hallbeck, Martin
    Linköping University, Department of Clinical and Experimental Medicine, Division of Inflammation Medicine. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Center for Diagnostics, Department of Clinical Pathology and Clinical Genetics.
    Nath, Sangeeta
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Health Sciences.
    Spreading of Amyloid-β Peptides via Neuritic Cell-to-cell Transfer Is Dependent on Insufficient Cellular Clearance2014In: Neurobiology of Disease, ISSN 0969-9961, E-ISSN 1095-953X, Vol. 65, p. 82-92Article in journal (Refereed)
    Abstract [en]

    The spreading of pathology through neuronal pathways is likely to be the cause of the progressive cognitive loss observed in Alzheimer's disease (AD) and other neurodegenerative diseases. We have recently shown the propagation of AD pathology via cell-to-cell transfer of oligomeric amyloid beta (Aβ) residues 1-42 (oAβ1-42) using our donor-acceptor 3-D co-culture model. We now show that different Aβ-isoforms (fluorescently labeled 1-42, 3(pE)-40, 1-40 and 11-42 oligomers) can transfer from one cell to another. Thus, transfer is not restricted to a specific Aβ-isoform. Although different Aβ isoforms can transfer, differences in the capacity to clear and/or degrade these aggregated isoforms result in vast differences in the net amounts ending up in the receiving cells and the net remaining Aβ can cause seeding and pathology in the receiving cells. This insufficient clearance and/or degradation by cells creates sizable intracellular accumulations of the aggregation-prone Aβ1-42 isoform, which further promotes cell-to-cell transfer; thus, oAβ1-42 is a potentially toxic isoform. Furthermore, cell-to-cell transfer is shown to be an early event that is seemingly independent of later appearances of cellular toxicity. This phenomenon could explain how seeds for the AD pathology could pass on to new brain areas and gradually induce AD pathology, even before the first cell starts to deteriorate, and how cell-to-cell transfer can act together with the factors that influence cellular clearance and/or degradation in the development of AD.

  • 22.
    Dutta, Ravi Kumar
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Health Sciences.
    Welander, Jenny
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Health Sciences.
    Brauckhoff, Michael
    Haukeland University Hospital, Bergen; University of Bergen, Norway .
    Walz, Martin
    Klinikum Essen Mitte, Essen, Germany .
    Alesina, Piero
    Klinikum Essen Mitte, Essen, Germany .
    Arnesen, Thomas
    Haukeland University Hospital, Bergen; University of Bergen, Norway.
    Söderkvist, Peter
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Center for Diagnostics, Department of Clinical Pathology and Clinical Genetics.
    Gimm, Oliver
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Surgery in Linköping.
    Complementary somatic mutations of KCNJ5, ATP1A1, and ATP2B3 in sporadic aldosterone producing adrenal adenomas2014In: Endocrine-Related Cancer, ISSN 1351-0088, E-ISSN 1479-6821, Vol. 21, no 1, p. L1-L4Article in journal (Other academic)
    Abstract [en]

    n/a

  • 23.
    Eklund, Daniel
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Health Sciences.
    Welin, Amanda
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Health Sciences.
    Andersson, Henrik
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Health Sciences.
    Verma, Deepti
    Linköping University, Department of Clinical and Experimental Medicine, Division of Inflammation Medicine. Linköping University, Faculty of Health Sciences.
    Söderkvist, Peter
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Center for Diagnostics, Department of Clinical Pathology and Clinical Genetics.
    Stendahl, Olle
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Health Sciences.
    Särndahl, Eva
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Health Sciences.
    Lerm, Maria
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Health Sciences.
    Human gene variants linked to enhanced NLRP3 activity limit intramacrophage growth of Mycobacterium tuberculosis2014In: The Journal of infectious diseases, ISSN 1537-6613, Vol. 209, no 5, p. 749-753Article in journal (Refereed)
    Abstract [en]

    Activation of the NLRP3 inflammasome and subsequent generation of IL-1β is initiated in macrophages upon recognition of several stimuli. In the present work, we show that gain-of-function gene variants of inflammasome components known to predispose individuals to inflammatory disorders have a host-protective role during infection with Mycobacterium tuberculosis. By isolation of macrophages from patients and healthy blood donors with genetic variants in NLRP3 and CARD8 and subsequently infecting the cells by virulent M. tuberculosis, we show that these gene variants, combined, are associated with increased control of bacterial growth in human macrophages.

  • 24.
    Eriksson, Ida
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Experimental Pathology. Linköping University, Faculty of Health Sciences.
    Joosten, M.
    Linköping University, Department of Clinical and Experimental Medicine, Experimental Pathology. Linköping University, Faculty of Health Sciences.
    Roberg, Karin
    Linköping University, Department of Clinical and Experimental Medicine, Oto-Rhiono-Laryngology and Head & Neck Surgery. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Anaesthetics, Operations and Specialty Surgery Center, Department of Otorhinolaryngology in Linköping.
    Öllinger, Karin
    Linköping University, Department of Clinical and Experimental Medicine, Experimental Pathology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Center for Diagnostics, Department of Clinical Pathology and Clinical Genetics.
    The histone deacetylase inhibitor trichostatin A reduces lysosomal pH and enhances cisplatin-induced apoptosis2013In: Experimental Cell Research, ISSN 0014-4827, E-ISSN 1090-2422, Vol. 319, no 1, p. 12-20Article in journal (Refereed)
    Abstract [en]

    High activity of histone deacetylases (HDACs) has been documented in several types of cancer and may be associated with survival advantage. In a head and neck squamous cell carcinoma cell line, cisplatin-induced apoptosis was augmented by pretreatment with the HDAC inhibitor trichostatin Apoptosis was accompanied by lysosomal membrane permeabilization (LMP), as shown by immunoblotting of the lysosomal marker protease cathepsin B in extracted cytosol and by immunofluorescence. Moreover, LAMP-2 (lysosomal associated membrane protein-2) was translocated from lysosomal membranes and found in a digitonin extractable fraction together with cytosolic proteins and pretreatment with trichostatin A potentiated the release. Overall, protein level of LAMP-2 was decreased during cell death and, interestingly, inhibition of cysteine cathepsins, by the pan-cysteine cathepsin inhibitor zFA-FMK, prevented loss of LAMP-2. The importance of LAMP-2 for lysosomal membrane stability, was confirmed by showing that LAMP-2 knockout MEFs (mouse embryonic fibroblasts) were more sensitive to cisplatin as compared to the corresponding wildtype cells. Trichostatin A reduced lysosomal pH from 4.46 to 4.25 and cell death was prevented when lysosomal pH was increased by NH4Cl, or when inhibiting the activity of lysosomal proteases. We conclude that trichostatin A enhances cisplatin induced cell death by decreasing lysosomal pH, which augments cathepsin activity resulting in reduced LAMP-2 level, and might promote LMP.

  • 25.
    Falck, Anna-Karin
    et al.
    Lund University, Sweden .
    Bendahl, Par-Ola
    Lund University, Sweden .
    Chebil, Gunilla
    Lund University, Sweden .
    Olsson, Hans
    Linköping University, Department of Clinical and Experimental Medicine, Molecular and Immunological Pathology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Center for Diagnostics, Department of Clinical Pathology and Clinical Genetics.
    Ferno, Marten
    Lund University, Sweden .
    Ryden, Lisa
    Lund University, Sweden .
    Biomarker expression and St Gallen molecular subtype classification in primary tumours, synchronous lymph node metastases and asynchronous relapses in primary breast cancer patients with 10 years follow-up2013In: Breast Cancer Research and Treatment, ISSN 0167-6806, E-ISSN 1573-7217, Vol. 140, no 1, p. 93-104Article in journal (Refereed)
    Abstract [en]

    Molecular profiles of asynchronous breast cancer metastases are of clinical relevance to individual patients treatment, whereas the role of profiles in synchronous lymph node metastases is not defined. The present study aimed to assess individual biomarkers and molecular subtypes according to the St Gallen classification in primary breast tumours, synchronous lymph node metastases and asynchronous relapses and relate the results to 10-year breast cancer mortality (BCM). Tissue microarrays were constructed from archived tissue blocks of primary tumours (N = 524), synchronous lymph node metastases (N = 147) and asynchronous relapses (N = 36). The samples were evaluated by two independent pathologists according to oestrogen receptor (ER), progesterone receptor (PR), Ki67 and human epidermal growth factor receptor 2 (HER2) by immunohistochemistry and in situ hybridisation. The expression of biomarkers and molecular subtypes in the primary tumour was compared with that in the synchronous lymph node metastases and relapses, and related to 10-year BCM. Discordances were found between primary tumours and relapses (ER: p = 0.006, PR: p = 0.04, Ki67: p = 0.02, HER2: p = 0.02, St Gallen subtypes: p = 0.07) but not between primary tumours and metastatic lymph node. Prognostic information was gained by the molecular subtype classification in primary tumours and nodal metastases; triple negative subtype had the highest BCM compared with the luminal A subtype (primary tumours: HR 4.0; 95 % CI 2.0-8.2, p andlt; 0.001, lymph node metastases: HR 3.5; 95 % CI 1.3-9.7, p = 0.02). When a shift in subtype inherence between primary tumour and metastatic lymph node was identified, the prognosis seemed to follow the subtype of the lymph node. Molecular profiles are not stable throughout tumour progression in breast cancer. Prognostic information for individual patients appears to be available from the analysis of biomarker expression in synchronous metastatic lymph nodes. The study supports biomarker analysis also in asynchronous relapses.

  • 26.
    Fryland, Linda
    et al.
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Clinical Immunology.
    Havarinasab, Said
    Linköping University, Department of Clinical and Experimental Medicine, Molecular and Immunological Pathology. Linköping University, Faculty of Health Sciences.
    Jakobsson, Tobias
    Department of Molecular Biology, Umeå University, Umeå, Sweden.
    Bergström, Sven
    Department of Molecular Biology, Umeå University, Umeå, Sweden.
    Hultman, Per
    Linköping University, Department of Clinical and Experimental Medicine, Molecular and Immunological Pathology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Diagnostics, Department of Clinical Pathology and Clinical Genetics.
    Ekerfelt, Christina
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Clinical Immunology.
    Mapping of T-cell subsets in relation to disease course in experimental Borrelia burgdorferi infection2012Manuscript (preprint) (Other academic)
    Abstract [en]

    Resolution of Lyme borreliosis has previously been shown to be associated with a strong initial Th1 response, followed by a subsequent Th2 response,  shutting off inflammation. We mapped markers for Th1, Th2, Th17, cytotoxic and T regulatory subsets in a murine model, where the outcome of Borrelia (B.) burgdorferi sensu stricto (s.s.) infection was altered by immune-deviation towards Th2 by exposure to a subtoxic dose of mercury. Twenty-one B. burgdorferi s.s.-infected (Bb), 21 immune-deviated B. burgdorferi s.s.-infected (BbId), and seven control C3H/HeN mice were sacrificed on days 15, 28 and 43 post-infection (p.i.) with B. burgdorferi s.s. BbId mice had increased joint swelling compared with Bb at the height of the disease (28 p.i.), and also showed a trend for increased spirochaetal load that became significant on day 43 p.i. BbId had an increased histopathology score on day 28 p.i. compared with both earlier and later time points. mRNA expression of IL-4 (p=0.018), IL-10 (p=0.018) and EBI-3 (p=0.009) decreased in Bb mice, but not in BbId, over the course of infection. A trend for higher expression of IL-12p40 mRNA in Bb mice compared with BbId was seen late in the disease course, while BbId showed trends for higher levels of Foxp3 and GM-CSF. At the protein level, BbId showed decreased levels of CXCL9 compared to the Bb group on day 15 p.i (p=0.007). Bb mice showed increases of CXCL9 and CXCL10 at all time points compared with day 0 p.i. (p≤0.014), whereas BbId mice showed an initial decrease in both chemokines at day 15 p.i. compared with day 0 (p≤0.008). In conclusion, both the clinical signs of infection and the trends for increased expression of pro-inflammatory GM-CSF and T-regulatory marker Foxp3 in BbId mice suggested ongoing inflammation. Although our findings support the need for a strong Th1 response followed by anti-inflammatory response for optimal resolution, the anti-inflammatory response seems to be more complex than only dampening the inflammation by a Th1-antagonistic Th2 response.

  • 27.
    Garvin, Stina
    et al.
    Östergötlands Läns Landsting, Center for Diagnostics, Department of Clinical Pathology and Clinical Genetics. Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Anaesthetics, Operations and Specialty Surgery Center, Department of Otorhinolaryngology in Linköping.
    Tiefenböck, Katharina
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Anaesthetics, Operations and Specialty Surgery Center, Department of Otorhinolaryngology in Linköping.
    Farnebo, Lovisa
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Anaesthetics, Operations and Specialty Surgery Center, Department of Otorhinolaryngology in Linköping.
    Thunell, Lena
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Health Sciences.
    Farnebo, Marianne
    Karolinska Institute, Sweden.
    Roberg, Karin
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Anaesthetics, Operations and Specialty Surgery Center, Department of Otorhinolaryngology in Linköping.
    Nuclear expression of WRAP53 beta is associated with a positive response to radiotherapy and improved overall survival in patients with head and neck squamous cell carcinoma2015In: Oral Oncology, ISSN 1368-8375, E-ISSN 1879-0593, Vol. 51, no 1, p. 24-30Article in journal (Refereed)
    Abstract [en]

    Objectives: Today there are no reliable predictive markers for radiotherapy response in head and neck squamous cell carcinoma (HNSCC), leading to both under-and over-treatment of patients, personal suffering, and negative socioeconomic effects. Inherited mutation in WRAP53 beta (WD40 encoding RNA Antisense to p53), a protein involved in intracellular trafficking, dramatically increases the risk of developing HNSCC. The purpose of this study was to investigate whether WRAP53 beta can predict response to radiotherapy in patients with HNSCC. Materials and methods: Tumor biopsies from patients with HNSCC classified as responders or non-responders to radiotherapy were examined for the expression of the WRAP53 beta protein and single nucleotide polymorphisms in the corresponding gene employing immunohistochemistry and allelic discrimination, respectively. In addition, the effect of RNAi-mediated downregulation of WRAP53 beta on the intrinsic radiosensitivity of two HNSCC cell lines was assed using crystal violet and clonogenic assays. Results: Nuclear expression of WRAP53 beta was significantly associated with better response to radiotherapy and improved patient survival. Downregulation of WRAP53 beta with siRNA in vitro enhanced cellular resistance to radiation. Conclusions: Our findings suggest that nuclear expression of WRAP53 beta promotes tumor cell death in response to radiotherapy and is a promising predictor of radiotherapy response in patients with HNSCC.

  • 28.
    Gati, Istvan
    et al.
    Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Health Sciences.
    Danielsson, Olof
    Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Health Sciences.
    Gunnarsson, Cecilia
    Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Diagnostics, Department of Clinical Pathology and Clinical Genetics.
    Vrethem, Magnus
    Linköping University, Department of Clinical and Experimental Medicine, Neurology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Local Health Care Services in Central Östergötland, Department of Neurology.
    Häggqvist, Bo
    Linköping University, Department of Clinical and Experimental Medicine, Molecular and Immunological Pathology. Linköping University, Faculty of Health Sciences.
    Fredriksson, Bengt-Arne
    Linköping University, Department of Clinical and Experimental Medicine.
    Landtblom, Anne-Marie
    Linköping University, Department of Clinical and Experimental Medicine, Neurology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Local Health Care Services in Central Östergötland, Department of Neurology.
    Letter: Bent Spine Syndrome: A Phenotype of Dysferlinopathy or a Symptomatic DYSF Gene Mutation Carrier2012In: European Neurology, ISSN 0014-3022, E-ISSN 1421-9913, Vol. 67, no 5, p. 300-302Article in journal (Other academic)
    Abstract [en]

    n/a

  • 29.
    Gunnarsson, Cecilia
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Oncology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Diagnostics, Department of Clinical Pathology and Clinical Genetics.
    Jerevall, Piiha-Lotta
    Linköping University, Department of Clinical and Experimental Medicine, Oncology. Linköping University, Faculty of Health Sciences.
    Hammar, Karl
    Linköping University, Department of Computer and Information Science. Linköping University, The Institute of Technology.
    Olsson, Birgit
    Linköping University, Department of Clinical and Experimental Medicine, Oncology. Linköping University, Faculty of Health Sciences.
    Nordenskjöld, Bo
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Oncology. Östergötlands Läns Landsting, Centre of Surgery and Oncology, Department of Oncology UHL.
    Jansson, Agneta
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Oncology.
    Stål, Olle
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Oncology. Östergötlands Läns Landsting, Centre of Surgery and Oncology, Department of Oncology UHL.
    Amplification of HSD17B1 has prognostic significance in postmenopausal breast cancer2008In: Breast Cancer Research and Treatment, ISSN 0167-6806, E-ISSN 1573-7217, Vol. 108, no 1, p. 35-41Article in journal (Refereed)
    Abstract [en]

    In situ synthesis of estrogens is believed to be of great importance for the progression of breast cancer. In postmenopausal women most estrogens are synthesized in peripheral hormone-target tissues from circulating precursor steroids, by the enzymes involved in formation of active estrogens. One of the enzymes involved in this process is 17β-hydroxysteroid dehydrogenase (17β-HSD) type 1. This enzyme catalyzes the interconversion of estrone (E1) to the biologically more potent estradiol (E2). The gene coding for 17β-HSD type 1 (HSD17B1) is located at 17q12-21. The aim of this study was to investigate altered gene copy number of HSD17B1 in breast cancer. We used real-time PCR and examined 387 postmenopausal breast tumors for amplification of HSD17B1, and if an increased mRNA level of this enzyme is associated with amplification of the gene. We also investigated whether amplification of HSD17B1 has a prognostic value. There was a significant correlation between gene copy number of HSD17B1 and mRNA expression level (P = 0.00002). ER-positive patients with amplification of HSD17B1 showed lower breast cancer survival than patients without amplification (P = 0.025). Among ER-negative patients there was no significant correlation between increased gene copy number of HSD17B1 and prognosis. Furthermore, we found that amplification of the gene had prognostic significance in multivariate analysis adjusting for other clinicopathological variables. © 2007 Springer Science+Business Media, LLC.

  • 30.
    Gustafsson, Håkan
    et al.
    Linköping University, Center for Medical Image Science and Visualization (CMIV). Linköping University, Department of Medical and Health Sciences, Division of Radiological Sciences. Linköping University, Faculty of Health Sciences.
    Hallbeck, Martin
    Linköping University, Department of Clinical and Experimental Medicine, Division of Inflammation Medicine. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Center for Diagnostics, Department of Clinical Pathology and Clinical Genetics.
    Norell, M.
    Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Health Sciences.
    Lindgren, Mikael
    Norwegian University of Science and Technology, Trondheim, Norway.
    Engström, Maria
    Linköping University, Center for Medical Image Science and Visualization (CMIV). Linköping University, Department of Medical and Health Sciences, Division of Radiological Sciences. Linköping University, Faculty of Health Sciences.
    Rosén, Anders
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Health Sciences.
    Zachrisson, Helene
    Linköping University, Center for Medical Image Science and Visualization (CMIV). Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart and Medicine Center, Department of Clinical Physiology in Linköping.
    Fe(III) distribution varies substantially within and between atherosclerotic plaques2014In: Magnetic Resonance in Medicine, ISSN 0740-3194, E-ISSN 1522-2594, Vol. 2, no 71, p. 885-892Article in journal (Refereed)
    Abstract [en]

    PURPOSE:

    Vulnerable atherosclerotic plaques are structurally weak and prone to rupture, presumably due to local oxidative stress. Redox active iron is linked to oxidative stress and the aim of this study was to investigate the distribution of Fe(III) in carotid plaques and its relation to vulnerability for rupture.

    METHODS:

    Atherosclerotic plaques from 10 patients (three asymptomatic and seven symptomatic) were investigated. Plaque vulnerability was classified using ultrasound and immunohistochemistry and correlated to Fe(III) measured by electron paramagnetic resonance spectroscopy.

    RESULTS:

    Large intra-plaque Fe(III) variations were found. Plaques from symptomatic patients had a higher Fe(III) concentration as compared with asymptomatic plaques (0.36 ± 0.21 vs. 0.06 ± 0.04 nmol Fe(III)/mg tissue, P < 0.05, in sections adjoining narrowest part of the plaques). All but one plaque from symptomatic patients showed signs of cap rupture. No plaque from asymptomatic patients showed signs of cap rupture. There was a significant increase in cap macrophages in plaques from symptomatic patients compared with asymptomatic patients (31 ± 11% vs. 2.3 ± 2.3%, P < 0.01).

    CONCLUSION:

    Fe(III) distribution varies substantially within atherosclerotic plaques. Plaques from symptomatic patients had significantly higher concentrations of Fe(III), signs of cap rupture and increased cap macrophage activity.

  • 31.
    Hadimeri, U.
    et al.
    Kärnsjukhuset, Skövde, Sweden.
    Hultman, Per
    Linköping University, Department of Clinical and Experimental Medicine, Division of Inflammation Medicine. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Center for Diagnostics, Department of Clinical Pathology and Clinical Genetics.
    Larsson, R.
    Östergötlands Läns Landsting, Heart and Medicine Center, Department of Nephrology.
    Melander, S.
    Östergötlands Läns Landsting, Heart and Medicine Center, Department of Nephrology.
    Mölne, J.
    Sahlgrenska University Hospital, Göteborg, Sweden.
    Hadimeri, H.
    Kärnsjukhuset, Skövde, Sweden.
    Membranoproliferative Glomerulonephritis and Inflammatory Pseudotumour of the Spleen2013In: Case Reports in Oncology, ISSN 1662-6575, E-ISSN 1662-6575, Vol. 6, no 1, p. 84-89Article in journal (Refereed)
    Abstract [en]

    Inflammatory pseudotumour is a rare condition that can affect various organs. The clinical and histologic appearance of the pseudotumour may mimic haematological, lymphoproliferative, paraneoplastic or malignant processes. A previously healthy 39-year-old man presented with nephrotic syndrome. He had a history of headaches, nausea and swollen ankles. Computed tomography of the abdomen revealed a 6-cm mass in the spleen. Following a renal biopsy, a diagnosis of membranoproliferative glomerulonephritis (MPGN) type I was made. Splenectomy was performed and the examination revealed a mixed population of lymphocytes with predominantly T-cells, B-cells and lymphoplasmacytoid cells. Immunostaining confirmed that the small cells were mostly T-cells positive for all T-cell markers including CD2, CD3, CD4, CD5, CD7 and CD8. A diagnosis of inflammatory pseudotumour was established. The removal of the spleen was followed by remission of glomerulonephritis, but it was complicated by a subphrenic abscess and pneumonia. This association between an inflammatory pseudotumour of the spleen and MPGN has not been previously described. Abnormal immune response due to the inflammation leading to secondary glomerulonephritis might be the main pathogenic mechanism.

  • 32.
    Haj-Hosseini, Neda
    et al.
    Linköping University, Department of Biomedical Engineering, Biomedical Instrumentation. Linköping University, The Institute of Technology.
    Richter, Johan
    Linköping University, Department of Biomedical Engineering. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Anaesthetics, Operations and Specialty Surgery Center, Department of Neurosurgery.
    Olivecrona, Magnus
    Department of Neurosurgery, Umeå University.
    Hillman, Jan
    Linköping University, Department of Clinical and Experimental Medicine, Neurosurgery. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Anaesthetics, Operations and Specialty Surgery Center, Department of Neurosurgery.
    Hallbeck, Martin
    Linköping University, Department of Clinical and Experimental Medicine, Experimental Pathology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Center for Diagnostics, Department of Clinical Pathology and Clinical Genetics.
    Wårdell, Karin
    Linköping University, Department of Biomedical Engineering, Biomedical Instrumentation. Linköping University, The Institute of Technology.
    Fluorescence guided spectroscopy versus fluorescence microscopy for brain tumor resection2013Conference paper (Other academic)
  • 33.
    Hallbeck, Martin
    et al.
    Östergötlands Läns Landsting, Center for Diagnostics, Department of Clinical Pathology and Clinical Genetics. Linköping University, Department of Clinical and Experimental Medicine, Division of Inflammation Medicine. Linköping University, Faculty of Health Sciences.
    Nath, Sangeeta
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuroscience. Linköping University, Faculty of Health Sciences.
    Marcusson, Jan
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuroscience. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Local Health Care Services in Central Östergötland, Department of Geriatric Medicine in Linköping.
    Neuron-to-Neuron Transmission of Neurodegenerative Pathology2013In: The Neuroscientist, ISSN 1073-8584, E-ISSN 1089-4098, Vol. 19, no 6, p. 560-566Article, review/survey (Refereed)
    Abstract [en]

    One of the hallmarks of neurodegenerative dementia diseases is the progressive loss of mental functions and the ability to manage activities of daily life. This progression is caused by the spread of the disease to more and more brain areas via anatomical connections. The pathophysiological process responsible for this spread of disease has long been sought after. There has been an increased understanding that the driving force of these neurodegenerative diseases could be the small, soluble intraneuronal accumulations of neurodegenerative proteins rather than the large, extracellular accumulations. Recently we have shown that the mechanism of spread of Alzheimer's disease most likely depends on the neuron-to-neuron spread of such soluble intraneuronal accumulations of -amyloid through neuritic connections. Similar transmissions have been shown for several other neurodegenerative proteins but little is known about the cellular mechanisms and about any potential strategies that might stop this spread. Resolving these questions requires good cellular models. We have established a unique model of synaptic transmission between human neuronal-like cells, something that has previously been difficult to target. This opens the possibility of developing potential inhibitors of progression of these devastating diseases.

  • 34.
    Hayat Roshanai, Afsaneh
    et al.
    BMC, Sweden Uppsala University, Sweden .
    Lampic, Claudia
    Karolinska Institute, Sweden Uppsala University, Sweden .
    Ingvoldstad, Charlotta
    Uppsala University, Sweden .
    Stenmark-Askmalm, Marie
    Linköping University, Department of Clinical and Experimental Medicine, Oncology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Diagnostics, Department of Clinical Pathology and Clinical Genetics.
    Bjorvatn, Chathrine
    University of Bergen, Norway .
    Rosenquist, Richard
    Uppsala University, Sweden .
    Nordin, Karin
    University of Bergen, Norway Uppsala University, Sweden .
    What Information Do Cancer Genetic Counselees Prioritize?2012In: Journal of Genetic Counseling, ISSN 1059-7700, E-ISSN 1573-3599, Vol. 21, no 4, p. 510-526Article in journal (Refereed)
    Abstract [en]

    This study explored the informational needs of individuals attending genetic counseling for hereditary cancer, using a free-choice and a forced choice method. Prior to the consultation the informational needs of 334 counselees from Sweden and Norway were assessed by the QUOTE-gene (ca) questionnaire and by a study specific forced choice method, using Q-methodology. Questionnaire responses indicated that counselees major concerns pertained to the need to be taken seriously, to be provided with sufficient risk estimation and medical/genetic information and to be involved in the decision making process. Furthermore, prior to counseling, counselees noted that the counselors consideration and skillfulness were also extremely important. Analysis of the Q-sorting results revealed that counselees needs could be assigned to one of five groups: the "need for facts; caring communication and medical information; information and support in communicating the genetic information to others; practical care and practical/medical information". Particularly noteworthy, counselees with varying backgrounds characteristics prioritized different needs. Cancer genetic counselees probably have different needs due to their medical and demographic background when attending genetic counseling. Addressing counselees specific concerns more sufficiently and thereby increasing the overall effectiveness of the counseling session requires increased insight into individual needs, by for instance, utilizing screening methods such as QUOTE-gene (ca) prior to the counseling session.

  • 35.
    Henriksson, Pontus
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Health Sciences.
    Lof, M.
    Karolinska Institute, Sweden.
    Söderkvist, Peter
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Center for Diagnostics, Department of Clinical Pathology and Clinical Genetics.
    Forsum, Elisabet
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Health Sciences.
    Variation in the fat mass and obesity-related (FTO) genotype is not associated with body fatness in infants, but possibly with their length2014In: Pediatric Obesity, ISSN 2047-6302, E-ISSN 2047-6310, Vol. 9, no 5, p. E112-E115Article in journal (Refereed)
    Abstract [en]

    BackgroundData relating variation at the fat mass and obesity-related (FTO) locus (rs9939609) to fat mass in infancy are inconclusive. ObjectiveTo study relationships between FTO genotype and infant size (at 1 and 12 weeks and at 1 year of age) and body composition (at 1 and 12 weeks). MethodsBody composition was assessed using air displacement plethysmography in 207 infants. FTO was genotyped using the TaqMan assay. ResultsThe number of risk alleles was related to length at 1 and 12 weeks (P=0.007-0.033) but not to fat mass. The relationship to length was stronger in boys than in girls. ConclusionsOur results suggest that the FTO genotype is not related during infancy to fat mass but is related to length in boys but not in girls.

  • 36.
    Hulten, M A.
    et al.
    University of Warwick, England .
    Jonasson, Jon
    Linköping University, Department of Clinical and Experimental Medicine, Molecular and Immunological Pathology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Diagnostics, Department of Clinical Pathology and Clinical Genetics.
    Iwarsson, E
    Karolinska Institute, Sweden .
    Uppal, P
    Imperial Coll School Med, England .
    Vorsanova, S G.
    Rosmedtechnol, Russia .
    Yurov, Y B.
    Rosmedtechnol, Russia .
    Iourov, I Y.
    Rosmedtechnol, Russia .
    Trisomy 21 Mosaicism: We May All Have a Touch of Down Syndrome2013In: Cytogenetic and Genome Research, ISSN 1424-8581, E-ISSN 1424-859X, Vol. 139, no 3, p. 189-192Article in journal (Refereed)
    Abstract [en]

    Ever increasing sophistication in the application of new analytical technology has revealed that our genomes are much more fluid than was contemplated only a few years ago. More specifically, this concerns interindividual variation in copy number (CNV) of structural chromosome aberrations, i.e. microdeletions and microduplications. It is important to recognize that in this context, we still lack basic knowledge on the impact of the CNV in normal cells from individual tissues, including that of whole chromosomes (aneuploidy). Here, we highlight this challenge by the example of the very first chromosome aberration identified in the human genome, i.e. an extra chromosome 21 (trisomy 21, T21), which is causative of Down syndrome (DS). We consider it likely that most, if not all, of us are T21 mosaics, i.e. everyone carries some cells with an extra chromosome 21, in some tissues. In other words, we may all have a touch of DS. We further propose that the occurrence of such tissue-specific T21 mosaicism may have important ramifications for the understanding of the pathogenesis, prognosis and treatment of medical problems shared between people with DS and those in the general non-DS population.

  • 37.
    Hulten, Maj Anita
    et al.
    University of Warwick, England Karolinska Institute, Sweden .
    Jonasson, Jon
    Linköping University, Department of Clinical and Experimental Medicine, Molecular and Immunological Pathology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Diagnostics, Department of Clinical Pathology and Clinical Genetics.
    Westgren, Magnus
    Karolinska Institute, Sweden .
    Jonsson, Anna Maria
    Karolinska Institute, Sweden .
    Papadogiannakis, Nikos
    Karolinska Institute, Sweden .
    Iwarsson, Erik
    Karolinska Institute, Sweden .
    Letter: Comment on "Origin of trisomy: no evidence to support the ovarian mosaicism theory"2012In: Prenatal Diagnosis, ISSN 0197-3851, E-ISSN 1097-0223, Vol. 32, no 12, p. 1221-1221Article in journal (Other academic)
    Abstract [en]

    n/a

  • 38.
    Hultman, Per
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Inflammation Medicine. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Center for Diagnostics, Department of Clinical Pathology and Clinical Genetics.
    Pollard, K. Michael
    Department of Molecular and Experimental Medicine, Scripps Research Institute, La Jolla, CA.
    Immunotoxicology of metals2014In: Handbook on the toxicology of metals, / [ed] Gunnar Nordberg, Bruce Fowler, Monica Nordberg, Academic Press, 2014, 4, p. 379-298Chapter in book (Refereed)
  • 39.
    Häggqvist, Bo
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Molecular and Immunological Pathology. Linköping University, Faculty of Health Sciences.
    Hultman, Per
    Linköping University, Department of Clinical and Experimental Medicine, Division of Inflammation Medicine. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Center for Diagnostics, Department of Clinical Pathology and Clinical Genetics.
    Interleukin-10 in murine mercury-induced systemic autoimmunity2005In: Clinical and Experimental Immunology, ISSN 0009-9104, E-ISSN 1365-2249, Vol. 141, no 3, p. 422-431Article in journal (Refereed)
    Abstract [en]

    Systemic autoimmune diseases have a complicated and largely unknown etiology and pathogenesis, but they are at least partly obeying the rules of an ordinary immune response. Cytokines are therefore important in the pathogenesis as demonstrated by the recent success in treating rheumatoid arthritis with anti-cytokine agents. The suppressive fimctions in the immune system have lately received much interest. One of the cytokines in focus in this respect is IL-10. We recently observed that in heavy-metal induced systemic autoimmunity, genetically resistant mice show a strong increase in IL-10 mRNA expression, which was not seen in susceptible mice. We have therefore examined the possible regulating effect of IL-10 on induction and manifestation of systemic autoimmunity in this model. We took two approaches: a targeted mutation for the IL-10 gene in a strain resistant to heavy-metal induced autoimmunity, and treatment with recombinant IL-10 in the genetically susceptible A. SW strain during the induction of autoimmunity by metals.

    The wild-type C57BL/6J (B6-WT) strain did not react with lymphoproliferation, polyclonal B-cell activation, increases in antinuclear autoantibodies (ANA) or tissue immune-complex (IC) deposits in response to inorganic mercury (Hg) or silver (Ag). However, in agreement with previous obsetvations there was a modest increase in serum IgG1, IgE and IgG2a. Treatment with Ag caused only a weak increase in IgE and IgG1. The B6.129P2-µ10tm1Cgn /J strain (IL-10 deficient B6 mice) did not develop antinucleolar antibodies (ANoA) during Hg treatment, but compared with Hg-treated B6-WT mice there was a significant increase in homogeneous ANA and a higher serum IgE concentration. The IL-10 deficient B6 controls showed a spontaneous increase in splenic weight as well as serum IgM and IgG1 compared with the B6-WT control mice. These signs of immune activation were also present in the IL-10 deficient B6 mice treated with Hg, while treatment with Ag reduced these features making the response similar to that in the B6-WT controls.

    The susceptible A.SW mice treated with rIL-10 and Hg showed during ongoing intense rIL-10 treatment reduced induction of ANoA, reduction in antichromatin antibodies (ACA), and a reduced increase in serum IgE compared with mice which received Hg but not rIL-10. In conclusion, the reduced ANoA induction during riL-10 treatment indicates suppressive effect of IL-10 on autoimmune development. Lack of IL-10 may promote development of ANA, ACA, and serum IgE, but is not likely to be crucial for resistance to heavy-metal induced autoimmunity.

  • 40.
    Jakobsen Falk, Ingrid
    et al.
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Medical and Health Sciences, Division of Drug Research.
    Willander, Kerstin
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Haematology.
    Chaireti, Roza
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Local Health Care Services in Central Östergötland, Department of Acute Internal Medicine.
    Lund, Johan
    Division of hematology, Department of Medicine, Karolinska Institutet, Huddinge, Stockholm, Sweden.
    Monica, Hermanson
    Department of Immunology, Genetics and Pathology, Rudbeck Laboratory, Uppsala University, Uppsala, Sweden.
    Gréen, Henrik
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Health Sciences. Department of Forensic Genetics and Forensic Toxicology, National Board of Forensic Medicine, Linköping, Sweden.
    Lotfi, Kourosh
    Linköping University, Department of Medical and Health Sciences. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting.
    Söderkvist, Peter
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Center for Diagnostics, Department of Clinical Pathology and Clinical Genetics.
    TP53 mutations identify a subgroup of AML patients with dramatically impaired outcome2014Manuscript (preprint) (Other academic)
    Abstract [en]

    TP53 is commonly mutated in several cancers and confers treatment resistance and poor prognosis. Altered expression of MDM2 (mouse double minute 2), a negative regulator of p53, may also attenuate normal p53 signaling, thereby enhancing tumor transformation and resistance to apoptosis. The single nucleotide polymorphism (SNP) 309 has been reported to increase MDM2 expression and impair normal p53 response. We investigated the frequency and impact of TP53 mutations (TP53mut) and MDM2SNP309 on treatment outcome and overall survival (OS) in 207 Swedish AML patients. We found a high frequency (22%) of TP53mut in patients with cytogenetic aberrations, with strong association to high risk cytogenetics (p<0.001). TP53mut patients had lower response rates compared to TP53 wild-type (wt) patients (22% and 76% CR, respectively, p<0.001) and reduced OS (5 and 21 months, respectively, p<0.001). In TP53wt patients with abnormal karyotype, the MDM2SNP309 conferred an impaired outcome, with patients carrying the alternative G allele  having shorter OS compared to T/T patients (13 and 29 months, p=0.031). In conclusion, our results show that TP53mut analysis as well as MDM2SNP309 genotyping may be useful tools for prognostication, risk stratification and selection of patients most likely to benefit from new drugs targeting the p53 signaling pathway.

  • 41.
    Jakubowska, A
    et al.
    Pomeranian Medical University, Poland .
    Rozkrut, D
    University of Szczecin, Poland .
    Antoniou, A
    University of Cambridge, England .
    Hamann, U
    Deutsch Krebsforschungszentrum DKFZ, Germany .
    Scott, R J
    University of Newcastle, Australia Hunter Medical Research Institute, Australia .
    McGuffog, L
    University of Cambridge, England .
    Healy, S
    Queensland Institute Medical Research, Australia .
    Sinilnikova, O M
    Centre Hospital University of Lyon, France University of Lyon 1, France .
    Rennert, G
    Technion Israel Institute Technology, Israel Technion Israel Institute Technology, Israel Technion Israel Institute Technology, Israel .
    Lejbkowicz, F
    Technion Israel Institute Technology, Israel Technion Israel Institute Technology, Israel Technion Israel Institute Technology, Israel .
    Flugelman, A
    Technion Israel Institute Technology, Israel Technion Israel Institute Technology, Israel Technion Israel Institute Technology, Israel .
    Andrulis, I L
    Cancer Care Ontario, Canada Mt Sinai Hospital, Canada .
    Glendon, G
    Cancer Care Ontario, Canada Mt Sinai Hospital, Canada .
    Ozcelik, H
    Mt Sinai Hospital, Canada .
    Thomassen, M
    Odense University Hospital, Denmark .
    Paligo, M
    University Hospital Pisa, Italy .
    Aretini, P
    University Hospital Pisa, Italy .
    Kantala, J
    Karolinska University Hospital, Sweden .
    Aroer, B
    Karolinska University Hospital, Sweden .
    Von Wachenfeldt, A
    Karolinska University Hospital, Sweden .
    Liljegren, A
    Karolinska University Hospital, Sweden .
    Loman, N
    University of Lund Hospital, Sweden .
    Herbst, K
    University of Lund Hospital, Sweden .
    Kristoffersson, U
    University of Lund Hospital, Sweden .
    Rosenquist, R
    Uppsala University, Sweden .
    Karlsson, P
    Sahlgrens University Hospital, Sweden .
    Stenmark-Askmalm, Marie
    Linköping University, Department of Clinical and Experimental Medicine, Oncology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Diagnostics, Department of Clinical Pathology and Clinical Genetics.
    Melin, B
    Umeå University, Sweden .
    Nathanson, K L
    University of Penn, PA 19104 USA University of Penn, PA 19104 USA .
    Domchek, S M
    University of Penn, PA 19104 USA University of Penn, PA 19104 USA .
    Byrski, T
    Pomeranian Medical University, Poland .
    Huzarski, T
    Pomeranian Medical University, Poland .
    Gronwald, J
    Pomeranian Medical University, Poland .
    Menkiszak, J
    Pomeranian Medical University, Poland .
    Cybulski, C
    Pomeranian Medical University, Poland .
    Serrano, P
    Pomeranian Medical University, Poland .
    Osorio, A
    Spanish National Cancer Research Centre, Spain Spanish National Cancer Research Centre, Spain .
    Cajal, T R
    Hospital Santa Creu and Sant Pau, Spain .
    Tsitlaidou, M
    National Centre Science Research Demokritos, Greece .
    Benitez, J
    Spanish National Cancer Research Centre, Spain Spanish National Cancer Research Centre, Spain .
    Gilbert, M
    Deutsch Krebsforschungszentrum DKFZ, Germany .
    Rookus, M
    Netherlands Cancer Institute, Netherlands .
    Aalfs, C M
    University of Amsterdam, Netherlands .
    Kluijt, I
    Netherlands Cancer Institute, Netherlands .
    Boessenkool-Pape, J L
    Netherlands Cancer Institute, Netherlands .
    Meijers-Heijboer, H E J
    Vrije University of Amsterdam Medical Centre, Netherlands .
    C Oosterwijk, J
    University of Groningen, Netherlands .
    J van Asperen, C
    Leiden University of Medical Centre, Netherlands .
    J Blok, M
    University Hospital Maastricht, Netherlands .
    R Nelen, M
    Radboud University of Nijmegen Medical Centre, Netherlands .
    M W van den Ouweland, A
    Erasmus MC, Netherlands .
    Seynaeve, C
    Erasmus MC, Netherlands .
    B van der Luijt, R
    University of Medical Centre Utrecht, Netherlands .
    Devilee, P
    Leiden University of Medical Centre, Netherlands Leiden University of Medical Centre, Netherlands .
    F Easton, D
    University of Cambridge, England .
    Peock, S
    University of Cambridge, England .
    Frost, D
    University of Cambridge, England .
    Platte, R
    University of Cambridge, England .
    D Ellis, S
    University of Cambridge, England .
    Fineberg, E
    University of Cambridge, England .
    G Evans, D
    NHS Fdn Trust, England .
    Lalloo, F
    NHS Fdn Trust, England .
    Eeles, R
    Royal Marsden NHS Fdn Trust, England .
    Jacobs, C
    Guys and St Thomas NHS Fdn Trust, England .
    Adlard, J
    Yorkshire Regional Genet Serv, England .
    Davidson, R
    Yorkhill Hospital, Scotland .
    Eccles, D
    University of Southampton, England .
    Cole, T
    Birmingham Womens Hospital Healthcare NHS Trust, England .
    Cook, J
    Sheffield Childrens Hospital, England .
    Godwin, A
    University of Kansas Medical Centre, KS USA .
    Bove, B
    Fox Chase Cancer Centre, PA 19111 USA .
    Stoppa-Lyonnet, D
    Institute Curie, France Institute Curie, France University of Paris 05, France .
    Caux-Moncoutier, V
    Institute Curie, France .
    Belotti, M
    Institute Curie, France .
    Tirapo, C
    Institute Curie, France .
    Mazoyer, S
    University of Lyon 1, France .
    Barjhoux, L
    University of Lyon 1, France .
    Boutry-Kryza, N
    Centre Hospital University of Lyon, France .
    Pujol, P
    CHU Arnaud de Villeneuve, France CRCM dAurelle, France .
    Coupier, I
    CHU Arnaud de Villeneuve, France CRLCC Val dAurelle, France .
    Peyrat, J-P
    Centre Oscar Lambret, France .
    Vennin, P
    Centre Oscar Lambret, France .
    Muller, D
    CLCC Paul Strauss, France .
    Fricker, J-P
    CLCC Paul Strauss, France .
    Venat-Bouvet, L
    Centre Hospital University of Dupuytren, France .
    Johannsson, OTh
    Landspitali University Hospital, Iceland University of Iceland, Iceland .
    Isaacs, C
    Georgetown University, DC USA .
    Schmutzler, R
    University Hospital Cologne, Germany University Hospital Cologne, Germany .
    Wappenschmidt, B
    University Hospital Cologne, Germany University Hospital Cologne, Germany .
    Meindl, A
    University of Munich, Germany .
    Arnold, N
    University of Kiel, Germany .
    Varon-Mateeva, R
    Institute Human Genet, Germany .
    Niederacher, D
    University of Dusseldorf, Germany .
    Sutter, C
    University of Heidelberg Hospital, Germany .
    Deissler, H
    University Hospital Ulm, Germany .
    Preisler-Adams, S
    University of Munster, Germany .
    Simard, J
    University of Laval, Canada Centre Hospital University of Quebec, Canada .
    Soucy, P
    University of Laval, Canada Centre Hospital University of Quebec, Canada .
    Durocher, F
    University of Laval, Canada Centre Hospital University of Quebec, Canada .
    Chenevix-Trench, G
    Queensland Institute Medical Research, Australia .
    Beesley, J
    Queensland Institute Medical Research, Australia .
    Chen, X
    Queensland Institute Medical Research, Australia .
    Rebbeck, T
    University of Penn, PA 19104 USA University of Penn, PA 19104 USA .
    Couch, F
    Mayo Clin, MN USA Mayo Clin, MN USA .
    Wang, X
    Mayo Clin, MN USA .
    Lindor, N
    Mayo Clin, MN USA .
    Fredericksen, Z
    Mayo Clin, MN USA .
    S Pankratz, V
    Mayo Clin, MN USA .
    Peterlongo, P
    Fdn IRCCS Ist Nazl Tumori INT, Italy Fdn Ist FIRC Oncology Mol, Italy .
    Bonanni, B
    Ist Europeo Oncol, Italy .
    Fortuzzi, S
    Fdn Ist FIRC Oncology Mol, Italy 84 Cogentech Cancer Genet Test Lab, Italy .
    Peissel, B
    Fdn IRCCS Ist Nazl Tumori INT, Italy .
    Szabo, C
    Mayo Clin, MN USA .
    L Mai, P
    Department Health and Human Serv, MD 20852 USA .
    T Loud, J
    Department Health and Human Serv, MD 20852 USA .
    Lubinski, J
    Pomeranian Medical University, Poland .
    Association of PHB 1630 C andgt; T and MTHFR 677 C andgt; T polymorphisms with breast and ovarian cancer risk in BRCA1/2 mutation carriers: results from a multicenter study2012In: British Journal of Cancer, ISSN 0007-0920, E-ISSN 1532-1827, Vol. 106, no 12, p. 2016-2024Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: The variable penetrance of breast cancer in BRCA1/2 mutation carriers suggests that other genetic or environmental factors modify breast cancer risk. Two genes of special interest are prohibitin (PHB) and methylene-tetrahydrofolate reductase (MTHFR), both of which are important either directly or indirectly in maintaining genomic integrity. less thanbrgreater than less thanbrgreater thanMETHODS: To evaluate the potential role of genetic variants within PHB and MTHFR in breast and ovarian cancer risk, 4102 BRCA1 and 2093 BRCA2 mutation carriers, and 6211 BRCA1 and 2902 BRCA2 carriers from the Consortium of Investigators of Modifiers of BRCA1 and BRCA2 (CIMBA) were genotyped for the PHB 1630 Candgt;T (rs6917) polymorphism and the MTHFR 677 Candgt;T (rs1801133) polymorphism, respectively. less thanbrgreater than less thanbrgreater thanRESULTS: There was no evidence of association between the PHB 1630 Candgt;T and MTHFR 677 Candgt;T polymorphisms with either disease for BRCA1 or BRCA2 mutation carriers when breast and ovarian cancer associations were evaluated separately. Analysis that evaluated associations for breast and ovarian cancer simultaneously showed some evidence that BRCA1 mutation carriers who had the rare homozygote genotype (TT) of the PHB 1630 Candgt;T polymorphism were at increased risk of both breast and ovarian cancer (HR 1.50, 95% CI 1.10-2.04 and HR 2.16, 95% CI 1.24-3.76, respectively). However, there was no evidence of association under a multiplicative model for the effect of each minor allele. less thanbrgreater than less thanbrgreater thanCONCLUSION: The PHB 1630TT genotype may modify breast and ovarian cancer risks in BRCA1 mutation carriers. This association need to be evaluated in larger series of BRCA1 mutation carriers.

  • 42.
    Jansson, Agneta
    et al.
    Linköping University, Department of Biomedicine and Surgery, Oncology. Linköping University, Faculty of Health Sciences.
    Carlsson, Jonas
    Linköping University, Department of Physics, Chemistry and Biology, Bioinformatics. Linköping University, The Institute of Technology.
    Olsson, Anette
    Linköping University, Department of Biomedicine and Surgery, Oncology. Linköping University, Faculty of Health Sciences.
    Storm, Petter
    Linköping University, Department of Biomedicine and Surgery, Oncology. Linköping University, Faculty of Health Sciences.
    Margolin, Sara
    Department of Oncology, Karolinska University Hospital/ Södersjukhuset, Stockholm, Sweden.
    Gunnarsson, Cecilia
    Linköping University, Department of Clinical and Experimental Medicine, Medical Genetics. Linköping University, Faculty of Health Sciences.
    Stenmark Askmalm, Marie
    Linköping University, Department of Clinical and Experimental Medicine, Oncology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Center for Diagnostics, Department of Clinical Pathology and Clinical Genetics.
    Lindblom, Annika
    Department of Molecular Medicine, Karolinska Institute, Stockholm, Sweden.
    Persson, Bengt
    Linköping University, Department of Physics, Chemistry and Biology, Bioinformatics. Linköping University, The Institute of Technology.
    Stål, Olle
    Linköping University, Department of Biomedicine and Surgery, Oncology. Linköping University, Faculty of Health Sciences.
    A new polymorphism in the coding region of exon four in HSD17B2 in relation to risk of sporadic and hereditary breast cancer2007In: Breast Cancer Research and Treatment, ISSN 0167-6806, E-ISSN 1573-7217, Vol. 106, no 1, p. 57-64Article in journal (Refereed)
    Abstract [en]

    In situ synthesis of oestrogens is of great importance in the development and progression of breast cancer. 17β-hydroxysteroid dehydrogenase (17HSD) type 2 catalyses oxidation from oestradiol to oestrone, and thereby protects the breast epithelial cells from oestradiol. Low expression of 17HSD type 2 has been associated with decreased survival in breast cancer, but no studies have investigated the mechanism behind the low expression. The 17HSD type 2 gene (HSD17B2) was screened for mutations with Single Stranded Conformation Polymorphism (SSCP)-DNA sequencing in 59 sporadic breast cancer cases, 19 hereditary breast cancer cases and seven breast cancer cell lines. DNA samples from 226 healthy individuals were used to identify if changes were previously unknown polymorphisms. No mutation was detected and therefore mutations in HSD17B2 do not explain why some breast tumours exhibit low 17HSD type 2 expression. However, a previously unknown polymorphism was found in exon four (Met226Val). Using molecular modelling, we found that the substituted residue is located at the outer part of the steroid binding site, probably causing minor alterations in the substrate binding. We further studied if the polymorphism contributes to breast cancer susceptibility in a larger material, but did not find an increased risk in the group of 317 sporadic breast cancer patients, 188 breast cancer patients with two close relatives with breast cancer or 122 hereditary breast cancer patients, compared to the healthy control group. We suggest that the detected polymorphism does not contribute to a higher risk of developing breast cancer.

  • 43.
    Jerhammar, Fredrik
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuroscience. Linköping University, Faculty of Health Sciences.
    Johansson, Ann-Charlotte
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuroscience. Linköping University, Faculty of Health Sciences. Not Found:Linkoping Univ, Fac Hlth Sci, Dept Clin and Expt Med, Div Otorhinolaryngol and Head and Neck Surg, Linkoping, Sweden .
    Ceder, Rebecca
    Karolinska Institute, Sweden .
    Welander, Jenny
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Health Sciences.
    Jansson, Agneta
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Health Sciences.
    Grafstrom, Roland C.
    Karolinska Institute, Sweden VTT Technical Research Centre Finland, Finland .
    Söderkvist, Peter
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Center for Diagnostics, Department of Clinical Pathology and Clinical Genetics.
    Roberg, Karin
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuroscience. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Anaesthetics, Operations and Specialty Surgery Center, Department of Otorhinolaryngology in Linköping.
    YAP1 is a potential biomarker for cetuximab resistance in head and neck cancer2014In: Oral Oncology, ISSN 1368-8375, E-ISSN 1879-0593, Vol. 50, no 9, p. 832-839Article in journal (Refereed)
    Abstract [en]

    Objectives: Targeted therapy against the epidermal growth factor receptor (EGFR) only variably represents a therapeutic advance in head and neck squamous cell carcinoma (HNSCC). This study addresses the need of biomarkers of treatment response to the EGFR-targeting antibody cetuximab (Erbitux (R)). Materials and Methods: The intrinsic cetuximab sensitivity of HNSCC cell lines was assessed by a crystal violet assay. Gene copy number analysis of five resistant and five sensitive cell lines was performed using the Affymetrix SNP 6.0 platform. Quantitative real-time PCR was used for verification of selected copy number alterations and assessment of mRNA expression. The functional importance of the findings on the gene and mRNA level was investigated employing siRNA technology. The data was statistically evaluated using Mann-Whitney U-test and Spearmans correlation test. Results: Analysis of the intrinsic cetuximab sensitivity of 32 HNSCC cell lines characterized five and nine lines as cetuximab sensitive or resistant, respectively. Gene copy number analysis of five resistant versus five sensitive cell lines identified 39 amplified protein-coding genes, including YAP1, in the genomic regions 11q22.1 or 5p13-15. Assessment using qPCR verified that YAP1 amplification associated with cetuximab resistance. Amplification of YAP1 correlated to higher mRNA levels, and RNA knockdown resulted in increased cetuximab sensitivity. Assessment of several independent clinical data sets in the public domain confirmed YAP1 amplifications in multiple tumor types including HNSCC, along with highly differential expression in a subset of HNSCC patients. Conclusion: Taken together, we provide evidence that YAP1 could represent a novel biomarker gene of cetuximab resistance in HNSCC cell lines.

  • 44.
    Johansson, Ida
    et al.
    Lund University, Sweden.
    Nilsson, Cecilia
    Central Hospital Vasteres, Sweden Uppsala University, Sweden .
    Berglund, Pontus
    Lund University, Sweden .
    Lauss, Martin
    Lund University, Sweden.
    Ringner, Markus
    Lund University, Sweden.
    Olsson, Hakan
    Lund University, Sweden .
    Luts, Lena
    Lund University, Sweden .
    Sim, Edith
    University of Oxford, England .
    Thorstensson, Sten
    Östergötlands Läns Landsting, Centre for Diagnostics, Department of Clinical Pathology and Clinical Genetics.
    Fjallskog, Marie-Louise
    Uppsala University, Sweden .
    Hedenfalk, Ingrid
    Lund University, Sweden .
    Gene expression profiling of primary male breast cancers reveals two unique subgroups and identifies N-acetyltransferase-1 (NAT1) as a novel prognostic biomarker2012In: Breast Cancer Research, ISSN 1465-5411, E-ISSN 1465-542X, Vol. 14, no 1Article in journal (Refereed)
    Abstract [en]

    Introduction: Male breast cancer (MBC) is a rare and inadequately characterized disease. The aim of the present study was to characterize MBC tumors transcriptionally, to classify them into comprehensive subgroups, and to compare them with female breast cancer (FBC). less thanbrgreater than less thanbrgreater thanMethods: A total of 66 clinicopathologically well-annotated fresh frozen MBC tumors were analyzed using Illumina Human HT-12 bead arrays, and a tissue microarray with 220 MBC tumors was constructed for validation using immunohistochemistry. Two external gene expression datasets were used for comparison purposes: 37 MBCs and 359 FBCs. less thanbrgreater than less thanbrgreater thanResults: Using an unsupervised approach, we classified the MBC tumors into two subgroups, luminal M1 and luminal M2, respectively, with differences in tumor biological features and outcome, and which differed from the intrinsic subgroups described in FBC. The two subgroups were recapitulated in the external MBC dataset. Luminal M2 tumors were characterized by high expression of immune response genes and genes associated with estrogen receptor (ER) signaling. Luminal M1 tumors, on the other hand, despite being ER positive by immunohistochemistry showed a lower correlation to genes associated with ER signaling and displayed a more aggressive phenotype and worse prognosis. Validation of two of the most differentially expressed genes, class 1 human leukocyte antigen (HLA) and the metabolizing gene N-acetyltransferase-1 (NAT1), respectively, revealed significantly better survival associated with high expression of both markers (HLA, hazard ratio (HR) 3.6, P = 0.002; NAT1, HR 2.5, P = 0.033). Importantly, NAT1 remained significant in a multivariate analysis (HR 2.8, P = 0.040) and may thus be a novel prognostic marker in MBC. less thanbrgreater than less thanbrgreater thanConclusions: We have detected two unique and stable subgroups of MBC with differences in tumor biological features and outcome. They differ from the widely acknowledged intrinsic subgroups of FBC. As such, they may constitute two novel subgroups of breast cancer, occurring exclusively in men, and which may consequently require novel treatment approaches. Finally, we identified NAT1 as a possible prognostic biomarker for MBC, as suggested by NAT1 positivity corresponding to better outcome.

  • 45.
    Johansson, Joel
    et al.
    Linköping University, Faculty of Health Sciences, Faculty of Health Sciences, Medical Programme.
    Ignatova, Simone
    Östergötlands Läns Landsting, Center for Diagnostics, Department of Clinical Pathology and Clinical Genetics. Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Health Sciences.
    Ekstedt, Mattias
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Gastroenterology and Hepatology. Östergötlands Läns Landsting, Heart and Medicine Center, Department of Gastroentorology.
    Pinworm infestation mimicking crohns' disease2013In: Case Reports in Gastrointestinal Medicine, ISSN 2090-6528, E-ISSN 2090-6536, Vol. 2013, article id 706197Article in journal (Refereed)
    Abstract [en]

    We here report a case of a young man who presented to his general practitioner with diarrhea. Inflammatory bowel disease was suspected and a colonoscopy showed aphthous lesions suggestive of Crohns' disease but biopsies revealed eggs of Enterobius vermicularis. When treated for this parasite, his symptoms were alleviated and a followup colonoscopy revealed a normal colon and distal ileum. Enterobius vermicularis is the most common parasite worldwide and has been attributed with many different presentations and pathologies. It is therefore necessary to maintain vigilance, even in high-income countries, in order to diagnose patients with one of the many atypical presentations of pinworms.

  • 46.
    Kirchhoff, Tomas
    et al.
    Mem Sloan Kettering Cancer Centre, USA.
    Gaudet, Mia M.
    Mem Sloan Kettering Cancer Centre, USA.
    Antoniou, Antonis C.
    University of Cambridge, England.
    McGuffog, Lesley
    University of Cambridge, England.
    Humphreys, Manjeet K.
    University of Cambridge, England.
    Dunning, Alison M.
    University of Cambridge, England.
    Bojesen, Stig E.
    University of Copenhagen, Denmark.
    Nordestgaard, Borge G.
    University of Copenhagen, Denmark University of Copenhagen, Denmark .
    Flyger, Henrik
    University of Copenhagen, Denmark .
    Kang, Daehee
    Seoul National University, South Korea National Cancer Centre, South Korea University of Ulsan, South Korea .
    Yoo, Keun-Young
    Seoul National University, South Korea National Cancer Centre, South Korea University of Ulsan, South Korea .
    Noh, Dong-Young
    Seoul National University, South Korea National Cancer Centre, South Korea University of Ulsan, South Korea .
    Ahn, Sei-Hyun
    Seoul National University, South Korea National Cancer Centre, South Korea University of Ulsan, South Korea .
    Dork, Thilo
    Hannover Medical Sch, Germany Hannover Medical Sch, Germany .
    Schuermann, Peter
    Hannover Medical Sch, Germany Hannover Medical Sch, Germany .
    H. Karstens, Johann
    Hannover Medical Sch, Germany Hannover Medical Sch, Germany .
    Hillemanns, Peter
    Hannover Medical Sch, Germany Hannover Medical Sch, Germany .
    J. Couch, Fergus
    Mayo Clin, MN USA Mayo Clin, MN USA .
    Olson, Janet
    Mayo Clin, MN USA .
    Vachon, Celine
    Mayo Clin, MN USA .
    Wang, Xianshu
    Mayo Clin, MN USA .
    Cox, Angela
    University of Sheffield, England .
    Brock, Ian
    University of Sheffield, England .
    Elliott, Graeme
    University of Sheffield, England .
    W. R. Reed, Malcolm
    University of Sheffield, England .
    Burwinkel, Barbara
    German Cancer Research Centre, Germany .
    Meindl, Alfons
    Technical University of Munich, Germany .
    Brauch, Hiltrud
    Dr Margarete Fischer Bosch Institute Clin Pharmacol, Germany University of Tubingen, Germany University of Tubingen, Germany .
    Hamann, Ute
    Deutsch Krebsforschungszentrum, Germany .
    Ko, Yon-Dschun
    Evangel Kliniken Bonn gGmbH, Germany .
    Broeks, Annegien
    Netherlands Cancer Institute, Netherlands Netherlands Cancer Institute, Netherlands Netherlands Cancer Institute, Netherlands .
    K. Schmidt, Marjanka
    Netherlands Cancer Institute, Netherlands Netherlands Cancer Institute, Netherlands Netherlands Cancer Institute, Netherlands .
    J. Van t Veer, Laura
    Netherlands Cancer Institute, Netherlands Netherlands Cancer Institute, Netherlands Netherlands Cancer Institute, Netherlands .
    M. Braaf, Linde
    Netherlands Cancer Institute, Netherlands Netherlands Cancer Institute, Netherlands Netherlands Cancer Institute, Netherlands .
    Johnson, Nichola
    Institute Cancer Research, England .
    Fletcher, Olivia
    Institute Cancer Research, England .
    Gibson, Lorna
    London School Hyg and Trop Med, England .
    Peto, Julian
    London School Hyg and Trop Med, England .
    Turnbull, Clare
    Institute Cancer Research, England .
    Seal, Sheila
    Institute Cancer Research, England .
    Renwick, Anthony
    Institute Cancer Research, England .
    Rahman, Nazneen
    Institute Cancer Research, England .
    Wu, Pei-Ei
    Academic Sinica, Taiwan .
    Yu, Jyh-Cherng
    Tri Serv Gen Hospital, Taiwan .
    Hsiung, Chia-Ni
    Academic Sinica, Taiwan .
    Shen, Chen-Yang
    Academic Sinica, Taiwan .
    C. Southey, Melissa
    University of Melbourne, Australia Cancer Council, Australia University of Melbourne, Australia .
    L. Hopper, John
    University of Melbourne, Australia .
    Hammet, Fleur
    University of Melbourne, Australia .
    Van Dorpe, Thijs
    Katholieke University of Leuven, Belgium .
    Dieudonne, Anne-Sophie
    Katholieke University of Leuven, Belgium .
    Hatse, Sigrid
    Katholieke University of Leuven, Belgium .
    Lambrechts, Diether
    Vesalius Research Centre, Belgium .
    L. Andrulis, Irene
    Cancer Care Ontario, Canada Mt Sinai Hospital, Canada University of Toronto, Canada .
    Bogdanova, Natalia
    NN Alexandrov Research Institute Oncology and Medical Radiol, Byelarus .
    Antonenkova, Natalia
    NN Alexandrov Research Institute Oncology and Medical Radiol, Byelarus .
    I. Rogov, Juri
    NN Alexandrov Research Institute Oncology and Medical Radiol, Byelarus .
    Prokofieva, Daria
    Russian Academic Science, Russia .
    Bermisheva, Marina
    Russian Academic Science, Russia .
    Khusnutdinova, Elza
    Russian Academic Science, Russia .
    J. van Asperen, Christi
    Leiden University, Netherlands .
    A. E. M. Tollenaar, Robert
    Leiden University, Netherlands .
    J. Hooning, Maartje
    Erasmus MC, Netherlands .
    Devilee, Peter
    Leiden University, Netherlands .
    Margolin, Sara
    Karolinska Institute, Sweden Karolinska University, Sweden .
    Lindblom, Annika
    Karolinska Institute, Sweden .
    L. Milne, Roger
    Spanish National Cancer Centre, Spain .
    Ignacio Arias, Jose
    Monte Naranco Hospital, Spain .
    Pilar Zamora, M.
    La Paz University Hospital, Spain .
    Benitez, Javier
    Spanish National Cancer Centre, Spain Centre Invest Biomed Red Enfermedades Rares, Spain .
    Severi, Gianluca
    Cancer Council, Australia University of Melbourne, Australia .
    Baglietto, Laura
    Cancer Council, Australia University of Melbourne, Australia .
    G. Giles, Graham
    Cancer Council, Australia University of Melbourne, Australia .
    B. Spurdle, Amanda
    Queensland Institute Medical Research, Australia Peter MacCallum Cancer Centre, Australia .
    Beesley, Jonathan
    Queensland Institute Medical Research, Australia Peter MacCallum Cancer Centre, Australia .
    Chen, Xiaoqing
    Queensland Institute Medical Research, Australia Peter MacCallum Cancer Centre, Australia .
    Holland, Helene
    Queensland Institute Medical Research, Australia Peter MacCallum Cancer Centre, Australia .
    Healey, Sue
    Queensland Institute Medical Research, Australia Peter MacCallum Cancer Centre, Australia .
    Wang-Gohrke, Shan
    University of Ulm, Germany .
    Chang-Claude, Jenny
    German Cancer Research Centre DFKZ, Germany .
    Mannermaa, Arto
    University of Eastern Finland, Finland Kuopio University Hospital, Finland .
    Kosma, Veli-Matti
    University of Eastern Finland, Finland Kuopio University Hospital, Finland .
    Kauppinen, Jaana
    University of Eastern Finland, Finland Kuopio University Hospital, Finland .
    Kataja, Vesa
    Vaasa Central Hospital, Finland Kuopio University Hospital, Finland .
    A. Agnarsson, Bjarni
    Landspitali University Hospital, Iceland University of Iceland, Iceland .
    A. Caligo, Maria
    University of Pisa, Italy Pisa University Hospital, Italy .
    K. Godwin, Andrew
    Fox Chase Cancer Centre, PA 19111 USA .
    Nevanlinna, Heli
    University of Helsinki, Finland .
    Heikkinen, Tuomas
    University of Helsinki, Finland .
    Fredericksen, Zachary
    Mayo Clin, MN USA .
    Lindor, Noralane
    Mayo Clin, MN USA .
    L. Nathanson, Katherine
    University of Penn, PA 19104 USA University of Penn, PA 19104 USA .
    M. Domchek, Susan
    University of Penn, PA 19104 USA University of Penn, PA 19104 USA .
    Loman, Niklas
    University of Lund Hospital, Sweden .
    Karlsson, Per
    Sahlgrens University Hospital, Sweden .
    Stenmark Askmalm, Marie
    Linköping University, Department of Clinical and Experimental Medicine, Oncology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Diagnostics, Department of Clinical Pathology and Clinical Genetics.
    Melin, Beatrice
    Umeå University, Sweden .
    von Wachenfeldt, Anna
    Karolinska University Hospital, Sweden .
    B. L. Hogervorst, Frans
    Netherlands Cancer Institute, Netherlands .
    Verheus, Martijn
    Netherlands Cancer Institute, Netherlands .
    A. Rookus, Matti
    Netherlands Cancer Institute, Netherlands .
    Seynaeve, Caroline
    Erasmus MC, Netherlands .
    A. Oldenburg, Rogier
    Erasmus MC, Netherlands .
    J. Ligtenberg, Marjolijn
    Radboud University of Nijmegen, Netherlands .
    G. E. M. Ausems, Margreet
    University of Medical Centre Utrecht, Netherlands .
    M. Aalfs, Cora
    Amsterdam Medical Centre, Netherlands .
    J. P. Gille, Hans
    Vrije University, Netherlands .
    T. Wijnen, Juul
    Vrije University, Netherlands .
    B. Gomez Garcia, Encarna
    University Hospital Maastricht, Netherlands .
    Peock, Susan
    University of Cambridge, England .
    Cook, Margaret
    University of Cambridge, England .
    T. Oliver, Clare
    University of Cambridge, England .
    Frost, Debra
    University of Cambridge, England .
    Luccarini, Craig
    University of Cambridge, England .
    Pichert, Gabriella
    Guys and St Thomas NHS Fdn Trust, England .
    Davidson, Rosemarie
    Yorkhill Hospital, Scotland .
    Chu, Carol
    Yorkshire Regional Genet Serv, England .
    Eccles, Diana
    Princess Anne Hospital, England .
    Ong, Kai-Ren
    Birmingham Womens Hospital Healthcare NHS Trust, England .
    Cook, Jackie
    Sheffield Childrens Hospital, England .
    Douglas, Fiona
    Newcastle Tyne Hospital NHS Trust, England .
    Hodgson, Shirley
    University of London, England .
    Gareth Evans, D.
    Central Manchester University Hospital National Health Serv NHS Fdn, England .
    Eeles, Rosalind
    Institute Cancer Research, England Royal Marsden NHS Fdn Trust, England .
    Gold, Bert
    NCI, MD USA .
    D. P. Pharoah, Paul
    University of Cambridge, England University of Cambridge, England .
    Offit, Kenneth
    Mem Sloan Kettering Cancer Centre, NY 10021 USA .
    Chenevix-Trench, Georgia
    Queensland Institute Medical Research, Australia Peter MacCallum Cancer Centre, Australia .
    F. Easton, Douglas
    University of Cambridge, England University of Cambridge, England .
    Breast Cancer Risk and 6q22.33: Combined Results from Breast Cancer Association Consortium and Consortium of Investigators on Modifiers of BRCA1/22012In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 7, no 6Article in journal (Refereed)
    Abstract [en]

    Recently, a locus on chromosome 6q22.33 (rs2180341) was reported to be associated with increased breast cancer risk in the Ashkenazi Jewish (AJ) population, and this association was also observed in populations of non-AJ European ancestry. In the present study, we performed a large replication analysis of rs2180341 using data from 31,428 invasive breast cancer cases and 34,700 controls collected from 25 studies in the Breast Cancer Association Consortium (BCAC). In addition, we evaluated whether rs2180341 modifies breast cancer risk in 3,361 BRCA1 and 2,020 BRCA2 carriers from 11 centers in the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA). Based on the BCAC data from women of European ancestry, we found evidence for a weak association with breast cancer risk for rs2180341 (per-allele odds ratio (OR) = 1.03, 95% CI 1.00-1.06, p = 0.023). There was evidence for heterogeneity in the ORs among studies (I-2 = 49.3%; p = less than0.004). In CIMBA, we observed an inverse association with the minor allele of rs2180341 and breast cancer risk in BRCA1 mutation carriers (per-allele OR = 0.89, 95% CI 0.80-1.00, p = 0.048), indicating a potential protective effect of this allele. These data suggest that that 6q22.33 confers a weak effect on breast cancer risk.

  • 47.
    Kishwar, Sultana
    et al.
    Linköping University, Department of Science and Technology, Physics and Electronics. Linköping University, The Institute of Technology.
    Siddique, M.
    Linköping University, Department of Science and Technology, Physics and Electronics. Linköping University, The Institute of Technology.
    Israr, Muhammad Qadir
    Linköping University, Department of Science and Technology, Physics and Electronics. Linköping University, The Institute of Technology.
    Nour, Omer
    Linköping University, Department of Science and Technology, Physics and Electronics. Linköping University, The Institute of Technology.
    Willander, Magnus
    Linköping University, Department of Science and Technology, Physics and Electronics. Linköping University, The Institute of Technology.
    Öllinger, Karin
    Linköping University, Department of Clinical and Experimental Medicine, Experimental Pathology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Center for Diagnostics, Department of Clinical Pathology and Clinical Genetics.
    Investigation of the phototoxic effect of ZnO nanorods on fibroblasts and melanoma human cells2014In: Laser Physics Letters, ISSN 1612-2011, E-ISSN 1612-202X, Vol. 11, no 11, article id 115606Article in journal (Refereed)
    Abstract [en]

    Photo-cytotoxicity of zinc oxide (ZnO) nanowires (NWs) either bare or conjugated with photosensitizers was studied in dark and after ultraviolet light exposure, in human melanoma and foreskin fibroblast cells. ZnO NWs were grown on the capillary tip and then coated with photosensitizer. This coated tip was used as pointer for intracellular insertion of ZnO NWs and photosensitizer. ZnO NWs pointer was inserted into a specific cell and then irradiated with ultraviolet (UVA), which led to loss of mitochondrial membrane potential, as estimated by loss of the Mitotracker Red staining. Dissolved ZnO NWs showed cytotoxicity as detected by MTT viability assay and morphological evaluation. UVA-irradiation enhanced the toxicity and caused the production of reactive oxygen species (ROS) resulting in cell necrosis. ZnO NWs were photo-toxic for both normal and cancer cells, questioning their bio-safety.

  • 48.
    Kissopoulou, Antheia
    et al.
    Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Health Sciences.
    Jonasson, Jon
    Linköping University, Department of Clinical and Experimental Medicine, Molecular and Immunological Pathology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Center for Diagnostics, Department of Clinical Pathology and Clinical Genetics.
    Lindahl, Tomas
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Center for Diagnostics, Department of Clinical Chemistry.
    Osman, Abdimajid
    Linköping University, Department of Clinical and Experimental Medicine, Clinical Chemistry. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Center for Diagnostics, Department of Clinical Chemistry.
    Next Generation Sequencing Analysis of Human Platelet PolyA plus mRNAs and rRNA-Depleted Total RNA2013In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 8, no 12, p. 81809-Article in journal (Refereed)
    Abstract [en]

    Background: Platelets are small anucleate cells circulating in the blood vessels where they play a key role in hemostasis and thrombosis. Here, we compared platelet RNA-Seq results obtained from polyA+ mRNA and rRNA-depleted total RNA. Materials and Methods: We used purified, CD45 depleted, human blood platelets collected by apheresis from three male and one female healthy blood donors. The Illumina HiSeq 2000 platform was employed to sequence cDNA converted either from oligo(dT) isolated polyA+ RNA or from rRNA-depleted total RNA. The reads were aligned to the GRCh37 reference assembly with the TopHat/Cufflinks alignment package using Ensembl annotations. A de novo assembly of the platelet transcriptome using the Trinity software package and RSEM was also performed. The bioinformatic tools HTSeq and DESeq from Bioconductor were employed for further statistical analyses of read counts. Results: Consistent with previous findings our data suggests that mitochondrially expressed genes comprise a substantial fraction of the platelet transcriptome. We also identified high transcript levels for protein coding genes related to the cytoskeleton function, chemokine signaling, cell adhesion, aggregation, as well as receptor interaction between cells. Certain transcripts were particularly abundant in platelets compared with other cell and tissue types represented by RNA-Seq data from the Illumina Human Body Map 2.0 project. Irrespective of the different library preparation and sequencing protocols, there was good agreement between samples from the 4 individuals. Eighteen differentially expressed genes were identified in the two sexes at 10% false discovery rate using DESeq. Conclusion: The present data suggests that platelets may have a unique transcriptome profile characterized by a relative over-expression of mitochondrially encoded genes and also of genomic transcripts related to the cytoskeleton function, chemokine signaling and surface components compared with other cell and tissue types. The in vivo functional significance of the non-mitochondrial transcripts remains to be shown.

  • 49.
    Koch, Andrea
    et al.
    Linköping University, Department of Medical and Health Sciences, Internal Medicine. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart and Medicine Centre, Allergy Centre UHL.
    Gustafsson, Bertil
    Linköping University, Department of Clinical and Experimental Medicine, Experimental Pathology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Diagnostics, Department of Clinical Pathology and Clinical Genetics.
    Fohlin, Helena
    Linköping University, Department of Clinical and Experimental Medicine, Oncology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Surgery, Orthopaedics and Cancer Treatment, Department of Oncology UHL.
    Sörenson, Sverre
    Linköping University, Department of Medical and Health Sciences, Pulmonary Medicine. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Surgery, Orthopaedics and Cancer Treatment, Department of Respiratory Medicine UHL.
    Cyclooxygenase-2 expression in lung cancer cells evaluated by immunocytochemistry2011In: Diagnostic Cytopathology, ISSN 8755-1039, E-ISSN 1097-0339, Vol. 39, no 3, p. 188-193Article in journal (Refereed)
    Abstract [en]

    Cyclooxygenase-2 (COX-2) expression may be a prognostic factor in lung cancer. In previous studies, COX-2 expression has almost exclusively been evaluated with immunohistochemical methods performed on histology sections of tissue biopsies. However, in clinical practice, lung cancer is often diagnosed with cytological techniques only. We present methodology and results from analysis of COX-2 expression with immunochemistry on cytological material in 53 patients with lung cancer. Preparation and staining with the method established at our laboratory were easy to perform and resulted in good quality slides. The percentage COX-2-stained cells and the intensity of staining varied widely between and within the different cases. The proportion of positively stained tumor cells was as follows: <1% in 20 patients, 1-10% in 7 patients, 11-50% in 17 patients, and more than 50% in 9 patients. In 17 cases, groups of cells with different intensity of COX-2 staining were found in the same slide. In conclusion, immunocytochemical analysis of COX-2 expression is technically easy to perform with routine diagnostic procedures. There is a great variation in the proportion of COX-2-positive cells among patients and in the intensity of staining among individual cells in many single cases. Diagn. Cytopathol.2011;39:188-193. © 2010 Wiley-Liss, Inc.

  • 50.
    Kugelberg, Johan
    et al.
    Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Health Sciences.
    Welander, Jenny
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Health Sciences.
    Schiavi, Francesca
    Veneto Institute Oncology IRCCS, Italy .
    Fassina, Ambrogio
    University of Padua, Italy .
    Backdahl, Martin
    Karolinska Institute, Sweden .
    Larsson, Catharina
    Karolinska Institute, Sweden .
    Opocher, Giuseppe
    Veneto Institute Oncology IRCCS, Italy University of Padua, Italy .
    Söderkvist, Peter
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Center for Diagnostics, Department of Clinical Pathology and Clinical Genetics.
    Dahia, Patricia L.
    University of Texas Health Science Centre San Antonio, TX 78229 USA .
    Neumann, Hartmut P. H.
    University of Freiburg, Germany .
    Gimm, Oliver
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Surgery in Linköping.
    Role of SDHAF2 and SDHD in von Hippel-Lindau Associated Pheochromocytomas2014In: World Journal of Surgery, ISSN 0364-2313, E-ISSN 1432-2323, Vol. 38, no 3, p. 724-732Article in journal (Refereed)
    Abstract [en]

    Background Pheochromocytomas (PCCs) develop from the adrenal medulla and are often part of a hereditary syndrome such as von Hippel-Lindau (VHL) syndrome. In VHL, only about 30 % of patients with a VHL missense mutation develop PCCs. Thus, additional genetic events leading to formation of such tumors in patients with VHL syndrome are sought. SDHAF2 (previously termed SDH5) and SDHD are both located on chromosome 11q and are required for the function of mitochondrial complex II. While SDHAF2 has been shown to be mutated in patients with paragangliomas (PGLs), SDHD mutations have been found both in patients with PCCs and in patients with PGLs. Materials and methods Because loss of 11q is a common event in VHL-associated PCCs, we aimed to investigate whether SDHAF2 and SDHD are targets. In the present study, 41 VHL-associated PCCs were screened for mutations and loss of heterozygosity (LOH) in SDHAF2 or SDHD. Promoter methylation, as well as mRNA expression of SDHAF2 and SDHD, was studied. In addition, immunohistochemistry (IHC) of SDHB, known to be a universal marker for loss of any part the SDH complex, was conducted. Results and conclusions LOH was found in more than 50 % of the VHL-associated PCCs, and was correlated with a significant decrease (p less than 0.05) in both SDHAF2 and SDHD mRNA expression, which may be suggestive of a pathogenic role. However, while SDHB protein expression as determined by IHC in a small cohort of tumors was lower in PCCs than in the surrounding adrenal cortex, there was no obvious correlation with LOH or the level of SDHAF2/SDHD mRNA expression. In addition, the lack of mutations and promoter methylation in the investigated samples indicates that other events on chromosome 11 might be involved in the development of PCCs in association with VHL syndrome.

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